Search

Your search keyword '"Maurizio, Scaltriti"' showing total 423 results
Start Over Author "Maurizio, Scaltriti"
423 results on '"Maurizio, Scaltriti"'

1. Shifting the paradigm in personalized cancer care through next‐generation therapeutics and computational pathology

Author

Jorge S. Reis‐Filho, Maurizio Scaltriti, Ansh Kapil, Hadassah Sade, and Susan Galbraith

Subjects
antibody drug conjugates, artificial intelligence, biomarkers, computational pathology, deep learning, digital pathology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

The incorporation of novel therapeutic agents such as antibody‐drug conjugates, radio‐conjugates, T‐cell engagers, and chimeric antigen receptor cell therapies represents a paradigm shift in oncology. Cell‐surface target quantification, quantitative assessment of receptor internalization, and changes in the tumor microenvironment (TME) are essential variables in the development of biomarkers for patient selection and therapeutic response. Assessing these parameters requires capabilities that transcend those of traditional biomarker approaches based on immunohistochemistry, in situ hybridization and/or sequencing assays. Computational pathology is emerging as a transformative solution in this new therapeutic landscape, enabling detailed assessment of not only target presence, expression levels, and intra‐tumor distribution but also of additional phenotypic features of tumor cells and their surrounding TME. Here, we delineate the pivotal role of computational pathology in enhancing the efficacy and specificity of these advanced therapeutics, underscoring the integration of novel artificial intelligence models that promise to revolutionize biomarker discovery and drug development.

Published
2024
Full Text
View/download PDF

2. High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

Author

Marta Palafox, Laia Monserrat, Meritxell Bellet, Guillermo Villacampa, Abel Gonzalez-Perez, Mafalda Oliveira, Fara Brasó-Maristany, Nusaibah Ibrahimi, Srinivasaraghavan Kannan, Leonardo Mina, Maria Teresa Herrera-Abreu, Andreu Òdena, Mònica Sánchez-Guixé, Marta Capelán, Analía Azaro, Alejandra Bruna, Olga Rodríguez, Marta Guzmán, Judit Grueso, Cristina Viaplana, Javier Hernández, Faye Su, Kui Lin, Robert B. Clarke, Carlos Caldas, Joaquín Arribas, Stefan Michiels, Alicia García-Sanz, Nicholas C. Turner, Aleix Prat, Paolo Nuciforo, Rodrigo Dienstmann, Chandra S. Verma, Nuria Lopez-Bigas, Maurizio Scaltriti, Monica Arnedos, Cristina Saura, and Violeta Serra

Subjects
Science
Abstract

CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects.

Published
2022
Full Text
View/download PDF

3. The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers

Author

Ezra Y. Rosen, Helen H. Won, Youyun Zheng, Emiliano Cocco, Duygu Selcuklu, Yixiao Gong, Noah D. Friedman, Ino de Bruijn, Onur Sumer, Craig M. Bielski, Casey Savin, Caitlin Bourque, Christina Falcon, Nikeysha Clarke, Xiaohong Jing, Fanli Meng, Catherine Zimel, Sophie Shifman, Srusthi Kittane, Fan Wu, Marc Ladanyi, Kevin Ebata, Jennifer Kherani, Barbara J. Brandhuber, James Fagin, Eric J. Sherman, Natasha Rekhtman, Michael F. Berger, Maurizio Scaltriti, David M. Hyman, Barry S. Taylor, and Alexander Drilon

Subjects
Science
Abstract

The results of the phase 1/2 LIBRETTO-001 clinical trial has recently established the efficacy of the RET inhibitor selpercatinib in RET-driven cancers. Here, the authors characterize the molecular determinants of response and resistance in 72 LIBRETTO-001 lung and thyroid cancer patients treated at a single site.

Published
2022
Full Text
View/download PDF

4. Recurrence biomarkers of triple negative breast cancer treated with neoadjuvant chemotherapy and anti-EGFR antibodies

Author

Nina Radosevic-Robin, Pier Selenica, Yingjie Zhu, Helen H. Won, Michael F. Berger, Lorenzo Ferrando, Emiliano Cocco, Maud Privat, Flora Ponelle-Chachuat, Catherine Abrial, Jean-Marc Nabholtz, Frederique Penault-Llorca, Jorge S. Reis-Filho, and Maurizio Scaltriti

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract To find metastatic recurrence biomarkers of triple-negative breast cancer (TNBC) treated by neoadjuvant chemotherapy and anti-EGFR antibodies (NAT), we evaluated tumor genomic, transcriptomic, and immune features, using MSK-IMPACT assay, gene arrays, Nanostring technology, and TIL assessment on H&E. Six patients experienced a rapid fatal recurrence (RR) and other 6 had later non-fatal recurrences (LR). Before NAT, RR had low expression of 6 MHC class I and 13 MHC class II genes but were enriched in upregulated genes involved in the cell cycle-related pathways. Their TIL number before NAT in RR was very low (

Published
2021
Full Text
View/download PDF

5. Canakinumab as treatment for COVID-19-related pneumonia: A prospective case-control study

Author

Daniele Generali, Giancarlo Bosio, Fabio Malberti, Antonio Cuzzoli, Sophie Testa, Laura Romanini, Antonio Fioravanti, Alessandro Morandini, Luca Pianta, Guglielmo Giannotti, Erika Maria Viola, Matteo Giorgi-Pierfranceschi, Marina Foramitti, Rosa Angela Tira, Ilaria Zangrandi, Giulia Chiodelli, Andrea Machiavelli, Maria Rosa Cappelletti, Alessia Giossi, Valeria De Giuli, Chiara Costanzi, Chiara Campana, Ottavia Bernocchi, Marianna Sirico, Alessia Zoncada, Alfredo Molteni, Sergio Venturini, Fabiola Giudici, Maurizio Scaltriti, and Angelo Pan

Subjects
COVID-19, Pneumonia, SARS-CoV-2, Canakinumab, Infectious and parasitic diseases, RC109-216
Abstract

Objectives: Canakinumab is an IL-1β antibody that neutralises the activity of IL-1β. This study examined the efficacy and safety of canakinumab in patients with moderate COVID-19-related pneumonia. Design: This study aimed to evaluate the reduction in duration of hospitalisation with adequate oxygen status. Forty-eight patients with moderate COVID-19-related pneumonia were asked to participate in the prospective case-control study: 33 patients (cases) signed informed consent and received canakinumab (Cohort 1) and 15 patients (Controls) refused to receive the experimental drug and received institutional standard of care (Cohort 2). Results: Hospital discharge within 21 days was seen in 63% of patients in Cohort 1 vs. 0% in Cohort 2 (median 14 vs. 26 days, respectively; p < 0.001). There was significant clinical improvement in ventilation regimes following administration of canakinumab compared with Cohort 2 (Stuart-Maxwell test for paired data, p < 0.001). Patients treated with canakinumab experienced a significant increase in PaO2:FiO2 (p < 0.001) and reduction in lung damage by CT (p = 0.01), along with significant decreases in immune/inflammation markers that were not observed in Cohort 2. Only mild side-effects were seen in patients treated with canakinumab; survival at 60 days was 90.0% (95% CI 71.9–96.7) in patients treated with canakinumab and 73.3% (95% CI 43.6–89.1) for Cohort 2. Conclusions: Treatment with canakinumab in patients with COVID-19-related pneumonia rapidly restored normal oxygen status, decreased the need for invasive mechanical ventilation, and was associated with earlier hospital discharge and favourable prognosis versus standard of care.

Published
2021
Full Text
View/download PDF

6. Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors

Author

Konstantinos V. Floros, Sheeba Jacob, Richard Kurupi, Carter K. Fairchild, Bin Hu, Madhavi Puchalapalli, Jennifer E. Koblinski, Mikhail G. Dozmorov, Sosipatros A. Boikos, Maurizio Scaltriti, and Anthony C. Faber

Subjects
Cytology, QH573-671
Abstract

Abstract Human epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy of HER2 inhibitors is mitigated by uniformly low levels of the myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have demonstrated that clinically advanced cyclin-dependent kinase (CDK) inhibitors are effective MCL-1 inhibitors in patients, and, importantly, well tolerated. We, therefore, tested whether the CDK inhibitor, dinaciclib, could block MCL-1 in preclinical HER2-amplified breast cancer models and therefore sensitize these cancers to dual HER2/EGFR inhibitors neratinib and lapatinib, as well as to the novel selective HER2 inhibitor tucatinib. Indeed, we found dinaciclib suppresses MCL-1 RNA and is highly effective at sensitizing HER2 inhibitors both in vitro and in vivo. This combination was tolerable in vivo. Mechanistically, liberating the effector BCL-2 protein, BAK, from MCL-1 results in robust apoptosis. Thus, clinically advanced CDK inhibitors may effectively combine with HER2 inhibitors and present a chemotherapy-free therapeutic strategy in HER2-amplified breast cancer, which can be tested immediately in the clinic.

Published
2021
Full Text
View/download PDF

7. Personalized cancer therapy prioritization based on driver alteration co-occurrence patterns

Author

Lidia Mateo, Miquel Duran-Frigola, Albert Gris-Oliver, Marta Palafox, Maurizio Scaltriti, Pedram Razavi, Sarat Chandarlapaty, Joaquin Arribas, Meritxell Bellet, Violeta Serra, and Patrick Aloy

Subjects
Drug-response biomarkers, Driver co-occurrence networks, Precision oncology, Medicine, Genetics, QH426-470
Abstract

Abstract Identification of actionable genomic vulnerabilities is key to precision oncology. Utilizing a large-scale drug screening in patient-derived xenografts, we uncover driver gene alteration connections, derive driver co-occurrence (DCO) networks, and relate these to drug sensitivity. Our collection of 53 drug-response predictors attains an average balanced accuracy of 58% in a cross-validation setting, rising to 66% for a subset of high-confidence predictions. We experimentally validated 12 out of 14 predictions in mice and adapted our strategy to obtain drug-response models from patients’ progression-free survival data. Our strategy reveals links between oncogenic alterations, increasing the clinical impact of genomic profiling.

Published
2020
Full Text
View/download PDF

8. Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Author

Kwanghee Kim, Wenhuo Hu, François Audenet, Nima Almassi, Aphrothiti J. Hanrahan, Katie Murray, Aditya Bagrodia, Nathan Wong, Timothy N. Clinton, Shawn Dason, Vishnu Mohan, Sylvia Jebiwott, Karan Nagar, Jianjiong Gao, Alex Penson, Chris Hughes, Benjamin Gordon, Ziyu Chen, Yiyu Dong, Philip A. Watson, Ricardo Alvim, Arijh Elzein, Sizhi P. Gao, Emiliano Cocco, Alessandro D. Santin, Irina Ostrovnaya, James J. Hsieh, Irit Sagi, Eugene J. Pietzak, A. Ari Hakimi, Jonathan E. Rosenberg, Gopa Iyer, Herbert A. Vargas, Maurizio Scaltriti, Hikmat Al-Ahmadie, David B. Solit, and Jonathan A. Coleman

Subjects
Science
Abstract

The advancement of upper tract urothelial carcinoma (UTUC) research is hampered by the lack of disease-specific models. Here, the authors report patient derived xenograft and cell line models of UTUC, and show that these models retain the genomic and biological heterogeneity of human disease.

Published
2020
Full Text
View/download PDF

9. MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer

Author

Barak Rotblat, Andreas Mock, Jerome Fayette, Limor Cohen, Idan Cohen, Elena Voronov, Jebrane Bouaoud, Lucas Michon, Pierre Saintigny, Luc G T Morris, Manu Prasad, Jonathan Zorea, Sankar Jagadeeshan, Avital B Shnerb, Sooraj Mathukkada, Ofra Novoplansky, Mai Badarni, Ksenia M Yegodayev, Sapir Tzadok, Libor Brezina, Andy Karabajakian, Tomer Cooks, Irit Allon, Orr Dimitstein, Benzion Joshua, Dexin Kong, Maurizio Scaltriti, Yaron Carmi, Cristina Conde-Lopez, Jochen Hess, Ina Kurth, and Moshe Elkabets

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Although the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Therefore, we aimed to characterize the effect of MEK1/2 inhibition on the tumor microenvironment (TME) of MAPK-driven HNC, elucidate tumor-host interaction mechanisms facilitating immune escape on treatment, and apply rationale-based therapy combination immunotherapy and MEK1/2 inhibitor to induce tumor clearance.Methods Mouse syngeneic tumors and xenografts experiments were used to analyze tumor growth in vivo. Single-cell cytometry by time of flight, flow cytometry, and tissue stainings were used to profile the TME in response to trametinib (MEK1/2 inhibitor). Co-culture of myeloid-derived suppressor cells (MDSC) with CD8+ T cells was used to measure immune suppression. Overexpression of colony-stimulating factor-1 (CSF-1) in tumor cells was used to show the effect of tumor-derived CSF-1 on sensitivity to trametinib and anti-programmed death- 1 (αPD-1) in mice. In HNC patients, the ratio between CSF-1 and CD8A was measured to test the association with clinical benefit to αPD-1 and αPD-L1 treatment.Results Using preclinical HNC models, we demonstrated that treatment with trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the antitumor immunity of CD8+ T cells. Activation of CD8+ T cells by supplementation with αPD-1 antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to αPD-1-supplementation by attenuating the expression of tumor-derived CSF-1, which reduced the abundance of two CSF-1R+CD11c+ MDSC populations in the TME. In contrast, prolonged treatment with trametinib abolished the antitumor activity of αPD-1, because tumor cells undergoing the epithelial to mesenchymal transition in response to trametinib restored CSF-1 expression and recreated an immune-suppressive TME.Conclusion Our findings provide the rationale for testing the trametinib/αPD-1 combination in HNC and highlight the importance of sensitizing tumors to αPD-1 by using MEK1/2 to interfere with the tumor–host interaction. Moreover, we describe the concept that treatment of cancer with a targeted therapy transiently induces an immune-active microenvironment, and supplementation of immunotherapy during this time further activates the antitumor machinery to cause tumor elimination.

Published
2022
Full Text
View/download PDF

10. First Nationwide Molecular Screening Program in Spain for Patients With Advanced Breast Cancer: Results From the AGATA SOLTI-1301 Study

Author

Sonia Pernas, Patricia Villagrasa, Ana Vivancos, Maurizio Scaltriti, Jordi Rodón, Octavio Burgués, Paolo Nuciforo, Jordi Canes, Laia Paré, Marta Dueñas, Maria Vidal, Juan Miguel Cejalvo, Antonia Perelló, Antonio Llommbard-Cussac, Joan Dorca, Alvaro Montaño, Tomás Pascual, Mafalda Oliveira, Gloria Ribas, Inmaculada Rapado, Aleix Prat, and Eva Ciruelos

Subjects
breast cancer, molecular genetic, DNA sequence analyses, PAM50 subtype, molecular targeted therapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

BackgroundThe SOLTI-1301 AGATA study aimed to assess the feasibility of a multi-institutional molecular screening program to better characterize the genomic landscape of advanced breast cancer (ABC) and to facilitate patient access to matched-targeted therapies in Spain.MethodsDNA sequencing of 74 cancer-related genes was performed using FFPE tumor samples in three different laboratories with three different gene panels. A multidisciplinary advisory board prospectively recommended potential targeted treatments. The primary objective was to determine the success of matching somatic DNA alteration to an experimental drug/drug class.ResultsBetween September 2014 and July 2017, 305 patients with ABC from 10 institutions were enrolled. Tumor sequencing was successful in 260 (85.3%) patients. Median age was 54 (29-80); most tumors were hormone receptor-positive/HER2-negative (74%), followed by triple-negative (14.5%) and HER2-positive (11.5%). Ninety-seven (37%) tumor samples analyzed proceeded from metastatic sites. Somatic mutations were identified in 163 (62.7%) patients, mostly in PIK3CA (34%), TP53 (22%), AKT1 (5%), ESR1 (3%), and ERBB2 (3%) genes. Significant enrichment of AKT1 mutation was observed in metastatic versus primary samples (9% vs. 2%; p=0.01). Genome-driven cancer therapy was recommended in 45% (n=116) of successfully screened patients, 11% (n=13) of whom finally received it. Among these patients, 46.2% had a PFS of ≥6 months on matched therapy.ConclusionsAGATA is the first nationwide molecular screening program carried out in Spain and we proved that implementing molecular data in the management of ABC is feasible. Although these results are promising, only 11% of the patients with genome-driven cancer therapy received it.

Published
2021
Full Text
View/download PDF

11. Author Correction: High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

Author

Marta Palafox, Laia Monserrat, Meritxell Bellet, Guillermo Villacampa, Abel Gonzalez-Perez, Mafalda Oliveira, Fara Brasó-Maristany, Nusaibah Ibrahimi, Srinivasaraghavan Kannan, Leonardo Mina, Maria Teresa Herrera-Abreu, Andreu Òdena, Mònica Sánchez-Guixé, Marta Capelán, Analía Azaro, Alejandra Bruna, Olga Rodríguez, Marta Guzmán, Judit Grueso, Cristina Viaplana, Javier Hernández, Faye Su, Kui Lin, Robert B. Clarke, Carlos Caldas, Joaquín Arribas, Stefan Michiels, Alicia García-Sanz, Nicholas C. Turner, Aleix Prat, Paolo Nuciforo, Rodrigo Dienstmann, Chandra S. Verma, Nuria Lopez-Bigas, Maurizio Scaltriti, Monica Arnedos, Cristina Saura, and Violeta Serra

Subjects
Science
Published
2022
Full Text
View/download PDF

12. Solid pseudopapillary neoplasms of the pancreas are dependent on the Wnt pathway

Author

Pier Selenica, Nitya Raj, Rahul Kumar, David N. Brown, Oriol Arqués, Diane Reidy, David Klimstra, Matija Snuderl, Jonathan Serrano, Héctor G. Palmer, Britta Weigelt, Jorge S. Reis‐Filho, and Maurizio Scaltriti

Subjects
beta‐catenin, gene expression, methylation, pancreas, SPN, Wnt, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Solid pseudopapillary neoplasms (SPNs) are rare and relatively indolent tumors of the pancreas. While primary SPNs can be surgically resected, there are currently no therapies available for patients with advanced stage disease. Given that these tumors frequently carry CTNNB1 hotspot (recurrently mutated loci in a gene) mutations resulting in β‐catenin nuclear accumulation, it has been speculated that the Wnt pathway may be a driver in this disease. Here, we present a comprehensive “multi‐omics” study where the genome, transcriptome, and methylome of SPNs were analyzed. We found that SPNs are characterized by a low‐complexity genome where somatic mutations in CTNNB1, present in 100% of the cases, are the only actionable genomic lesions. Compared to more common subtypes of pancreatic tumors (adenocarcinomas and pancreatic neuroendocrine tumors), SPNs show high expression levels of genes belonging to the Wnt pathway. Their methylome was consistent with an epithelial cell origin and a general upregulation of Wnt pathway genes. Clinical studies to evaluate the exquisite sensitivity of SPNs to inhibitors of the Wnt pathway are warranted.

Published
2019
Full Text
View/download PDF

13. Author Correction: The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers

Author

Ezra Y. Rosen, Helen H. Won, Youyun Zheng, Emiliano Cocco, Duygu Selcuklu, Yixiao Gong, Noah D. Friedman, Ino de Bruijn, Onur Sumer, Craig M. Bielski, Casey Savin, Caitlin Bourque, Christina Falcon, Nikeysha Clarke, Xiaohong Jing, Fanli Meng, Catherine Zimel, Sophie Shifman, Srushti Kittane, Fan Wu, Marc Ladanyi, Kevin Ebata, Jennifer Kherani, Barbara J. Brandhuber, James Fagin, Eric J. Sherman, Natasha Rekhtman, Michael F. Berger, Maurizio Scaltriti, David M. Hyman, Barry S. Taylor, and Alexander Drilon

Subjects
Science
Published
2022
Full Text
View/download PDF

14. ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins

Author

Clara Alcon, Jorge Gómez Tejeda Zañudo, Reka Albert, Nikhil Wagle, Maurizio Scaltriti, Anthony Letai, Josep Samitier, and Joan Montero

Subjects
ER+ breast cancer, DBP, priming, apoptosis, targeted therapies, resistance, Cytology, QH573-671
Abstract

Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.

Published
2021
Full Text
View/download PDF

15. A network modeling approach to elucidate drug resistance mechanisms and predict combinatorial drug treatments in breast cancer

Author

Jorge Gómez Tejeda Zañudo, Maurizio Scaltriti, and Réka Albert

Subjects
Breast cancer, Signal transduction networks, Network model, Dynamic model, Resistance, Combination therapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Mechanistic models of within-cell signal transduction networks can explain how these networks integrate internal and external inputs to give rise to the appropriate cellular response. These models can be fruitfully used in cancer cells, whose aberrant decision-making regarding their survival or death, proliferation or quiescence can be connected to errors in the state of nodes or edges of the signal transduction network. Results Here we present a comprehensive network, and discrete dynamic model, of signal transduction in ER+ breast cancer based on the literature of ER+, HER2+, and PIK3CA-mutant breast cancers. The network model recapitulates known resistance mechanisms to PI3K inhibitors and suggests other possibilities for resistance. The model also reveals known and novel combinatorial interventions that are more effective than PI3K inhibition alone. Conclusions The use of a logic-based, discrete dynamic model enables the identification of results that are mainly due to the organization of the signaling network, and those that also depend on the kinetics of individual events. Network-based models such as this will play an increasing role in the rational design of high-order therapeutic combinations.

Published
2017
Full Text
View/download PDF

16. Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target

Author

Peter J. Cook, Rozario Thomas, Ram Kannan, Esther Sanchez de Leon, Alexander Drilon, Marc K. Rosenblum, Maurizio Scaltriti, Robert Benezra, and Andrea Ventura

Subjects
Science
Abstract

The use of mouse models has been an invaluable resource in cancer research but their generation is lengthy and costly. Here the authors describe an approach to generate engineered mouse models carrying specific gene fusions and, as a proof of principle, show that Bcan-Ntrk1 fusion leads to glioblastomas.

Published
2017
Full Text
View/download PDF

17. Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma

Author

Aviram Mizrachi, Yosi Shamay, Janki Shah, Samuel Brook, Joanne Soong, Vinagolu K. Rajasekhar, John L. Humm, John H. Healey, Simon N. Powell, José Baselga, Daniel A. Heller, Adriana Haimovitz-Friedman, and Maurizio Scaltriti

Subjects
Science
Abstract

Head and neck squamous cell carcinomas (HNSCC) often harbourPIK3CAmutations but PI3Kα inhibitors can cause some side effects. Here, the authors develop P-selectin targeted nanoparticles to enhance tumour-specific delivery of a PI3Kα inhibitor to HNSCC PDX and orthotopic xenograft models.

Published
2017
Full Text
View/download PDF

18. PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression

Author

Eneda Toska, Pau Castel, Sagar Chhangawala, Amaia Arruabarrena-Aristorena, Carmen Chan, Vasilis C. Hristidis, Emiliano Cocco, Mirna Sallaku, Guotai Xu, Jane Park, Gerard Minuesa, Sophie G. Shifman, Nicholas D. Socci, Richard Koche, Christina S. Leslie, Maurizio Scaltriti, and José Baselga

Subjects
Biology (General), QH301-705.5
Abstract

Summary: The PI3K pathway integrates extracellular stimuli to phosphorylate effectors such as AKT and serum-and-glucocorticoid-regulated kinase (SGK1). We have previously reported that the PI3K pathway regulates estrogen receptor (ER)-dependent transcription in breast cancer through the phosphorylation of the lysine methyltransferase KMT2D by AKT. Here, we show that PI3Kα inhibition, via a negative-feedback loop, activates SGK1 to promote chromatin-based regulation of ER-dependent transcription. PI3K/AKT inhibitors activate ER, which promotes SGK1 transcription through direct binding to its promoter. Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity. Thus, SGK1 regulates the chromatin landscape and ER-dependent transcription via the direct phosphorylation of KMT2D. These findings reveal an ER-SGK1-KMT2D signaling circuit aimed to attenuate ER response through a role for SGK1 to program chromatin and ER transcriptional output. : Toska, Castel, et al. show that the PI3K pathway propagates its effects to control chromatin and estrogen receptor (ER) function through SGK1, a PI3K effector. PI3K inhibitors, via a negative-feedback loop, activate SGK1, which phosphorylates the histone lysine methyltransferase KMT2D to attenuate its activity and regulate ER response. Keywords: SGK1, KMT2D, PI3K pathway, estrogen receptor, breast cancer, chromatin regulation, AKT, PI3K inhibitors

Published
2019
Full Text
View/download PDF

19. Antitumor activity of the PI3K δ-sparing inhibitor MEN1611 in PIK3CA mutated, trastuzumab-resistant HER2 + breast cancer

Author

Alessio Fiascarelli, Giuseppe Merlino, Stefania Capano, Simone Talucci, Diego Bisignano, Alessandro Bressan, Daniela Bellarosa, Corrado Carrisi, Alessandro Paoli, Mario Bigioni, Patrizia Tunici, Clelia Irrissuto, Massimiliano Salerno, Joaquin Arribas, Elisa de Stanchina, Maurizio Scaltriti, Monica Binaschi, Institut Català de la Salut, [Fiascarelli A, Merlino G, Capano S, Talucci S, Bisignano D, Bressan A] Menarini Group, Preclinical and Translational Sciences, Menarini Ricerche SpA, Pomezia, Rome, Italy. [Arribas J] Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. Preclinical and Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer, Monforte de Lemos, Madrid, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Cancer Research, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Oncology, acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas [COMPUESTOS QUÍMICOS Y DROGAS], Otros calificadores::/uso terapéutico [Otros calificadores], Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Mama - Càncer - Tractament, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::/therapeutic use [Other subheadings], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors [CHEMICALS AND DRUGS], Proteïnes quinases - Inhibidors - Ús terapèutic
Abstract

Purpose Dysregulation of the PI3K pathway is one of the most common events in breast cancer. Here we investigate the activity of the PI3K inhibitor MEN1611 at both molecular and phenotypic levels by dissecting and comparing its profile and efficacy in HER2 + breast cancer models with other PI3K inhibitors. Methods Models with different genetic backgrounds were used to investigate the pharmacological profile of MEN1611 against other PI3K inhibitors. In vitro studies evaluated cell viability, PI3K signaling, and cell death upon treatment with MEN1611. In vivo efficacy of the compound was investigated in cell line- and patient-derived xenografts models. Results Consistent with its biochemical selectivity, MEN1611 demonstrated lower cytotoxic activity in a p110δ-driven cellular model when compared to taselisib, and higher cytotoxic activity in the p110β-driven cellular model when compared to alpelisib. Moreover, MEN1611 selectively decreased the p110α protein levels in PIK3CA mutated breast cancer cells in a concentration- and proteasome-dependent manner. In vivo, MEN1611 monotherapy showed significant and durable antitumor activity in several trastuzumab-resistant PIK3CA-mutant HER2 + PDX models. The combination of trastuzumab and MEN1611 significantly improved the efficacy compared to single agent treatment. Conclusions The profile of MEN1611 and its antitumoral activity suggest an improved profile as compared to pan-inhibitors, which are limited by a less than ideal safety profile, and isoform selective molecules, which may potentially promote development of resistance mechanisms. The compelling antitumor activity in combination with trastuzumab in HER2 + trastuzumab-resistant, PIK3CA mutated breast cancer models is at the basis of the ongoing B-Precise clinical trial (NCT03767335).

Published
2023

20. Supplementary Figure Legends 1-6, Table Legend 1 from PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

Author

José Baselga, Maurizio Scaltriti, Leif W. Ellisen, Javier Cortés, Jordi Rodón, José Pérez, Isabel T. Rubio, Orland Díez, Claudia Aura, Maria Teresa Calvo, Olga Rodríguez, Judit Grueso, Marta Guzmán, Patricia Cozar, Pilar Anton, Aleix Prat, Kristine Torres-Lockhart, Lei He, Violeta Serra, Celina García-García, and Yasir H. Ibrahim

Abstract

PDF file - 58K

Published
2023
Full Text
View/download PDF

21. Supplementary Fig 6 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 6

Published
2023
Full Text
View/download PDF

22. Data from Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer

Author

Nikolaus Schultz, David B. Solit, Barry S. Taylor, Laura Tang, Michael F. Berger, David H. Ilson, Neal Rosen, Marc Ladanyi, Maurizio Scaltriti, David M. Hyman, Ahmet Zehir, Sumit Middha, Marinela Capanu, Mark E. Robson, Jinru Shia, Daniela Molena, David R. Jones, Valerie W. Rusch, Zsofia K. Stadler, Manjit Bains, Daniel G. Coit, Hans Gerdes, Mark Schattner, Vivian E. Strong, Liying Zhang, David P. Kelsen, Benjamin E. Gross, Zachary J. Heins, Jianjiong Gao, Efsevia Vakiani, Nancy Bouvier, Ritika Kundra, Yaelle Tuvy, Jamie C. Riches, Geoffrey Y. Ku, Jaclyn F. Hechtman, Walid K. Chatila, Philip Jonsson, Francisco Sanchez-Vega, and Yelena Y. Janjigian

Abstract

The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability–high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein–Barr virus–positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance.Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49–58. ©2017 AACR.See related commentary by Sundar and Tan, p. 14.See related article by Pectasides et al., p. 37.This article is highlighted in the In This Issue feature, p. 1

Published
2023
Full Text
View/download PDF

23. Figure S2 from Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer

Author

Nikolaus Schultz, David B. Solit, Barry S. Taylor, Laura Tang, Michael F. Berger, David H. Ilson, Neal Rosen, Marc Ladanyi, Maurizio Scaltriti, David M. Hyman, Ahmet Zehir, Sumit Middha, Marinela Capanu, Mark E. Robson, Jinru Shia, Daniela Molena, David R. Jones, Valerie W. Rusch, Zsofia K. Stadler, Manjit Bains, Daniel G. Coit, Hans Gerdes, Mark Schattner, Vivian E. Strong, Liying Zhang, David P. Kelsen, Benjamin E. Gross, Zachary J. Heins, Jianjiong Gao, Efsevia Vakiani, Nancy Bouvier, Ritika Kundra, Yaelle Tuvy, Jamie C. Riches, Geoffrey Y. Ku, Jaclyn F. Hechtman, Walid K. Chatila, Philip Jonsson, Francisco Sanchez-Vega, and Yelena Y. Janjigian

Abstract

Concordance between copy-number inferred from next generation sequencing and protein overexpression by IHC or gene amplification by FISH.

Published
2023
Full Text
View/download PDF

24. Supplementary Methods, References, Figures 1-4, Tables 1-3 from A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion–Positive Solid Tumors

Author

David M. Hyman, S. Michael Rothenberg, Steve Andrews, Barry S. Taylor, Jaclyn F. Hechtman, Michael F. Berger, Philip Jonsson, Alison M. Schram, Bethany Hanusch, Sandeep Raj, Ryma Benayed, Maurizio Scaltriti, Dorothea N. Douglas-Lindsay, Paul R. Gordon, Lance A. Wollenberg, Walter E. DeWolf, Francis X. Sullivan, Tony H. Morales, Andrew Parker, Wen-I Wu, Robyn Hamor, Shannon L. Winski, Karyn S. Bouhana, Paul D. Larsen, Barbara J. Brandhuber, Gabrielle R. Kolakowski, Veronique Lauriault, Steve Smith, Kevin Ebata, Brian B. Tuch, Nora Ku, James F. Blake, Ramamoorthy Nagasubramanian, and Alexander Drilon

Abstract

Supplementary Methods Supplementary References Supplementary Figure 1. Effect of acquired resistance mutations on TRK inhibitor activity. Supplementary Figure 2. Further characterization of LOXO-195 inhibitory activity against acquired resistance mutations. Supplementary Figure 3. LOXO-195 is selectively cytotoxic to TRK-fusion cell lines. Supplementary Figure 4. Identification of a clonal NTRK1 (TRKA)-G595R mutation after larotrectinib treatment. Supplementary Table 1. LOXO-195 ADME properties. Supplementary Table 2. Selectivity of LOXO-195 for 228 kinases. Supplementary Table 3. Summary of LOXO-195 PK parameters for each patient during intra-patient dose escalation.

Published
2023
Full Text
View/download PDF

25. Figure S1 from EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer

Author

Yelena Y. Janjigian, Nikolaus Schultz, Maurizio Scaltriti, Jorge A. Carrasquillo, David B. Solit, Jason S. Lewis, Barry S. Taylor, Elisa de Stanchina, Michael F. Berger, Wolfgang A. Weber, David H. Ilson, Christine A. Iacobuzio-Donahue, Heiko Schöder, Neeta Pandit-Taskar, Steven M. Larson, Richard B. Lanman, Rebecca J. Nagy, Todd Hembrough, Yuan Tian, Fabiola Cecchi, Besnik Qeriqi, Marissa Mattar, Marinela Capanu, Mario E. Lacouture, Karen Brown, Robert A. Lefkowitz, David P. Kelsen, Mark Schattner, Efsevia Vakiani, Joanne Soong, Gouri J. Nanjangud, Nancy Bouvier, Christopher J. Fong, Helen Won, Yaelle Tuvy, Geoffrey Y. Ku, Pau Castel, Jaclyn F. Hechtman, and Francisco Sanchez-Vega

Abstract

Additional results for dual probe EGFR and ERBB2 FISH from Patients 9, 30 and 32.

Published
2023
Full Text
View/download PDF

26. Supplementary Figure S2 from Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

Author

David M. Hyman, Funda Meric-Bernstam, David B. Solit, Barry S. Taylor, José Baselga, Richard Bryce, Alshad S. Lalani, Melanie Dujka, Lisa D. Eli, Feng Xu, Grace Mann, Maurizio Scaltriti, Yanyan Cai, Aliaksandra Samoila, Myra Melcer, S. Duygu Selcuklu, Catherine Zimel, Elena I. Gavrila, Komal Jhaveri, Sarat Chandarlapaty, Gary A. Ulaner, Rebecca J. Nagy, Richard B. Lanman, Alexander N. Gorelick, François-Clement Bidard, Andrés Cervantes, Xavier Gonzàlez-Farré, Lee S. Schwartzberg, Joohyuk Sohn, Valentina Boni, Victor Moreno, Monica Arnedos, Morten Mau-Sørensen, Iben Spanggaard, Adam M. Brufksy, Macarena I. de la Fuente, Carlos L. Arteaga, Ingrid A. Mayer, Dejan Juric, Geoffrey I. Shapiro, Janice Lu, Sherene Loi, Cristina Saura, Alison M. Schram, Helen H. Won, Sarina A. Piha-Paul, and Lillian M. Smyth

Abstract

Overall sequencing CONSORT diagram. Flow diagram of study patients and analyzed biospecimens processed through and selected for central sequencing using MSK-IMPACT and Guardant360. cfDNA, cell-free DNA; FFPE, formalin-fixed paraffin-embedded; MSK-IMPACT, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets; QC, quality control.

Published
2023
Full Text
View/download PDF

27. Supplementary Figure 3 from Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

Author

José Baselga, Claudia Aura, José Jimenez, Ludmila Prudkin, Varenka Rodriguez, Kip A. West, Kelly L. Slocum, Alice R. Lim, Olga Rodriguez, Marta Guzman, Emmanuel Normant, Violeta Serra, and Maurizio Scaltriti

Abstract

Supplementary Figure 3 from Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

Published
2023
Full Text
View/download PDF

28. Supplementary Fig 3 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 3

Published
2023
Full Text
View/download PDF

29. Data from TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors

Author

Maurizio Scaltriti, Alexander Drilon, Andrea Ventura, Chandra S. Verma, Elisa de Stanchina, Moshe Elkabets, David M. Hyman, Jaclyn F. Hechtman, Alberto Bardelli, Barry S. Taylor, Sandra Misale, Uwe Rix, Yi Liao, Sankar Jagadeeshan, Ofra Novoplansky, Michael F. Berger, Alexander N. Gorelick, Neil Vasan, Ram Kannan, Benedetta Mussolin, Sabrina Arena, Yanyan Cai, Fan Wu, Srushti Kittane, Amaia Arruabarrena-Aristorena, Eneda Toska, Laura Baldino, Amanda Kulick, Sophie Shifman, Helen H. Won, Alison M. Schram, Srinivasaraghavan Kannan, Ji Eun Lee, and Emiliano Cocco

Abstract

On-target resistance to next-generation TRK inhibitors in TRK fusion–positive cancers is largely uncharacterized. In patients with these tumors, we found that TRK xDFG mutations confer resistance to type I next-generation TRK inhibitors designed to maintain potency against several kinase domain mutations. Computational modeling and biochemical assays showed that TRKAG667 and TRKCG696 xDFG substitutions reduce drug binding by generating steric hindrance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors. Consistently, type II inhibitors impede the growth and TRK-mediated signaling of xDFG-mutant isogenic and patient-derived models. Collectively, these data demonstrate that adaptive conformational resistance can be abrogated by shifting kinase engagement modes. Given the prior identification of paralogous xDFG resistance mutations in other oncogene-addicted cancers, these findings provide insights into rational type II drug design by leveraging inhibitor class affinity switching to address recalcitrant resistant alterations.Significance:In TRK fusion–positive cancers, TRK xDFG substitutions represent a shared liability for type I TRK inhibitors. In contrast, they represent a potential biomarker of type II TRK inhibitor activity. As all currently available type II agents are multikinase inhibitors, rational drug design should focus on selective type II inhibitor creation.This article is highlighted in the In This Issue feature, p. 1

Published
2023
Full Text
View/download PDF

30. Supplementary Figure 3 from PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

Author

José Baselga, Maurizio Scaltriti, Leif W. Ellisen, Javier Cortés, Jordi Rodón, José Pérez, Isabel T. Rubio, Orland Díez, Claudia Aura, Maria Teresa Calvo, Olga Rodríguez, Judit Grueso, Marta Guzmán, Patricia Cozar, Pilar Anton, Aleix Prat, Kristine Torres-Lockhart, Lei He, Violeta Serra, Celina García-García, and Yasir H. Ibrahim

Abstract

PDF file - 301K, Combined PIK3CA siRNA and PARP suppression in TNBC cell lines

Published
2023
Full Text
View/download PDF

31. Data from Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

Author

David M. Hyman, Funda Meric-Bernstam, David B. Solit, Barry S. Taylor, José Baselga, Richard Bryce, Alshad S. Lalani, Melanie Dujka, Lisa D. Eli, Feng Xu, Grace Mann, Maurizio Scaltriti, Yanyan Cai, Aliaksandra Samoila, Myra Melcer, S. Duygu Selcuklu, Catherine Zimel, Elena I. Gavrila, Komal Jhaveri, Sarat Chandarlapaty, Gary A. Ulaner, Rebecca J. Nagy, Richard B. Lanman, Alexander N. Gorelick, François-Clement Bidard, Andrés Cervantes, Xavier Gonzàlez-Farré, Lee S. Schwartzberg, Joohyuk Sohn, Valentina Boni, Victor Moreno, Monica Arnedos, Morten Mau-Sørensen, Iben Spanggaard, Adam M. Brufksy, Macarena I. de la Fuente, Carlos L. Arteaga, Ingrid A. Mayer, Dejan Juric, Geoffrey I. Shapiro, Janice Lu, Sherene Loi, Cristina Saura, Alison M. Schram, Helen H. Won, Sarina A. Piha-Paul, and Lillian M. Smyth

Abstract

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib.Significance:HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.This article is highlighted in the In This Issue feature, p. 161

Published
2023
Full Text
View/download PDF

32. Supplementary Fig 2 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 2

Published
2023
Full Text
View/download PDF

33. Supplementary Figure 4 from PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

Author

José Baselga, Maurizio Scaltriti, Leif W. Ellisen, Javier Cortés, Jordi Rodón, José Pérez, Isabel T. Rubio, Orland Díez, Claudia Aura, Maria Teresa Calvo, Olga Rodríguez, Judit Grueso, Marta Guzmán, Patricia Cozar, Pilar Anton, Aleix Prat, Kristine Torres-Lockhart, Lei He, Violeta Serra, Celina García-García, and Yasir H. Ibrahim

Abstract

PDF file - 3.4MB, Concordance in ER, PR, HER2, and PTEN expression between original patient tumors and the derived tumor grafts

Published
2023
Full Text
View/download PDF

34. Supplementary Figures from TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors

Author

Maurizio Scaltriti, Alexander Drilon, Andrea Ventura, Chandra S. Verma, Elisa de Stanchina, Moshe Elkabets, David M. Hyman, Jaclyn F. Hechtman, Alberto Bardelli, Barry S. Taylor, Sandra Misale, Uwe Rix, Yi Liao, Sankar Jagadeeshan, Ofra Novoplansky, Michael F. Berger, Alexander N. Gorelick, Neil Vasan, Ram Kannan, Benedetta Mussolin, Sabrina Arena, Yanyan Cai, Fan Wu, Srushti Kittane, Amaia Arruabarrena-Aristorena, Eneda Toska, Laura Baldino, Amanda Kulick, Sophie Shifman, Helen H. Won, Alison M. Schram, Srinivasaraghavan Kannan, Ji Eun Lee, and Emiliano Cocco

Abstract

Supplementary Figures

Published
2023
Full Text
View/download PDF

35. Supplementary Methods, Tables 1 - 9, Figures 1 - 8 from Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer

Author

Levi A. Garraway, José Baselga, Maurizio Scaltriti, Pau Castel, Mahmoud Ghandi, Flora Luo, Daniel J. Treacy, Pedram Razavi, Rajee Antony, and Xiuning Le

Abstract

Supplementary Methods, Tables 1 - 9, Figures 1 - 8. Supplementary Table 1. Functional classification for validated genes. Supplementary Table 2. Validated 43 candidate genes' genetic alteration status in the invasive breast cancer (TCGA) database. Supplementary Table 3. Receptor status, mutational status and intrinsic subtypes of breast cancer cell lines used in this study. Supplementary Table 4. GI50 of BYL719 in different breast cancer cell lines with overexpression of PIM isoforms. Supplementary Table 5. PIM1 and AKT phosphorylation sites in PRAS40, BAD, p21 and p27. Supplementary Table 6. PIM gene expression levels in PIK3CA-mutant breast cancer cell lines. Supplementary Table 7. GI50 of BYL719 in the presence of LGH447 (1μM) or DMSO in PIK3CA-mutant breast cancer cell lines. Supplementary Table 8. Signature genes that changed concordantly in patient sample pairs and PIM signature. Supplementary Table 9. Hormonal receptor status by immunohistochemistry (IHC), HER2 status by FISH and IHC of PIM1 amplified or overexpressed breast cancer tumor samples from the invasive breast cancer (TCGA) database. Supplementary Figure 1. Lentiviral infection efficacy quality in the large-scale ORF screen. Supplementary Figure 2. PIM1 confers resistance to breast cancer cell lines with different PIK3CA mutations and various intrinsic subtypes. Supplementary Figure 3. PIM1 confers resistance to inhibitors targeting key components of PI3K pathway. Supplementary Figure 4. PIM1 inhibitors alone have minimal inhibitory effects on T47D cells with or without PIM1 overexpression. Supplementary Figure 5. PIM1 expression abrogates cell-cycle arrest in cells treated with BYL719. Supplementary Figure 6. BYL719 and AZD1208 or LGH447 demonstrated synergy in PIM1 expressing T47D cells. Supplementary Figure 7. PIM activation signature. Supplementary Figure 8. PIM and PI3K pathway genetic mutations showed mutual exclusivity in treatment-naive breast cancers.

Published
2023
Full Text
View/download PDF

36. Data from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.Significance:T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627

Published
2023
Full Text
View/download PDF

37. Supplementary Figure Legends from Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer

Author

Nikolaus Schultz, David B. Solit, Barry S. Taylor, Laura Tang, Michael F. Berger, David H. Ilson, Neal Rosen, Marc Ladanyi, Maurizio Scaltriti, David M. Hyman, Ahmet Zehir, Sumit Middha, Marinela Capanu, Mark E. Robson, Jinru Shia, Daniela Molena, David R. Jones, Valerie W. Rusch, Zsofia K. Stadler, Manjit Bains, Daniel G. Coit, Hans Gerdes, Mark Schattner, Vivian E. Strong, Liying Zhang, David P. Kelsen, Benjamin E. Gross, Zachary J. Heins, Jianjiong Gao, Efsevia Vakiani, Nancy Bouvier, Ritika Kundra, Yaelle Tuvy, Jamie C. Riches, Geoffrey Y. Ku, Jaclyn F. Hechtman, Walid K. Chatila, Philip Jonsson, Francisco Sanchez-Vega, and Yelena Y. Janjigian

Abstract

Text legends for Supplementary Figures S1-S4.

Published
2023
Full Text
View/download PDF

38. Supplementary Figure 1 from PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

Author

José Baselga, Maurizio Scaltriti, Leif W. Ellisen, Javier Cortés, Jordi Rodón, José Pérez, Isabel T. Rubio, Orland Díez, Claudia Aura, Maria Teresa Calvo, Olga Rodríguez, Judit Grueso, Marta Guzmán, Patricia Cozar, Pilar Anton, Aleix Prat, Kristine Torres-Lockhart, Lei He, Violeta Serra, Celina García-García, and Yasir H. Ibrahim

Abstract

PDF file - 195K, PI3K regulates BRCA expression

Published
2023
Full Text
View/download PDF

39. Supplementary Data from Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

Author

David M. Hyman, Funda Meric-Bernstam, David B. Solit, Barry S. Taylor, José Baselga, Richard Bryce, Alshad S. Lalani, Melanie Dujka, Lisa D. Eli, Feng Xu, Grace Mann, Maurizio Scaltriti, Yanyan Cai, Aliaksandra Samoila, Myra Melcer, S. Duygu Selcuklu, Catherine Zimel, Elena I. Gavrila, Komal Jhaveri, Sarat Chandarlapaty, Gary A. Ulaner, Rebecca J. Nagy, Richard B. Lanman, Alexander N. Gorelick, François-Clement Bidard, Andrés Cervantes, Xavier Gonzàlez-Farré, Lee S. Schwartzberg, Joohyuk Sohn, Valentina Boni, Victor Moreno, Monica Arnedos, Morten Mau-Sørensen, Iben Spanggaard, Adam M. Brufksy, Macarena I. de la Fuente, Carlos L. Arteaga, Ingrid A. Mayer, Dejan Juric, Geoffrey I. Shapiro, Janice Lu, Sherene Loi, Cristina Saura, Alison M. Schram, Helen H. Won, Sarina A. Piha-Paul, and Lillian M. Smyth

Abstract

Supplementary data

Published
2023
Full Text
View/download PDF

40. Supplementary Figure 2 from PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

Author

José Baselga, Maurizio Scaltriti, Leif W. Ellisen, Javier Cortés, Jordi Rodón, José Pérez, Isabel T. Rubio, Orland Díez, Claudia Aura, Maria Teresa Calvo, Olga Rodríguez, Judit Grueso, Marta Guzmán, Patricia Cozar, Pilar Anton, Aleix Prat, Kristine Torres-Lockhart, Lei He, Violeta Serra, Celina García-García, and Yasir H. Ibrahim

Abstract

PDF file - 208K, PI3K blockade suppresses BRCA1/2 transcription

Published
2023
Full Text
View/download PDF

41. Supplementary Fig 5 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 5

Published
2023
Full Text
View/download PDF

42. Supplementary Figure 5 from PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

Author

José Baselga, Maurizio Scaltriti, Leif W. Ellisen, Javier Cortés, Jordi Rodón, José Pérez, Isabel T. Rubio, Orland Díez, Claudia Aura, Maria Teresa Calvo, Olga Rodríguez, Judit Grueso, Marta Guzmán, Patricia Cozar, Pilar Anton, Aleix Prat, Kristine Torres-Lockhart, Lei He, Violeta Serra, Celina García-García, and Yasir H. Ibrahim

Abstract

PDF file - 162K, Western blot of cell lysates from MDA-MB-468 or PDC44 cells treated with 750nM and 500nM BKM120 respectively for 4 days using the indicated antibodies

Published
2023
Full Text
View/download PDF

43. Supplementary Table 1 from Clinical Response to a Lapatinib-Based Therapy for a Li-Fraumeni Syndrome Patient with a Novel HER2V659E Mutation

Author

José Baselga, Joan Seoane, Maurizio Scaltriti, Paolo Nuciforo, Ludmila Prudkin, Joaquín Arribas, Javier Hernández-Losa, Judit Grueso, Leticia De Mattos-Arruda, Josep-Lluís Parra, Ginevra Caratù, Daniel Silberschmidt, Enriqueta Felip, Xose S. Puente, Ana Vivancos, and Violeta Serra

Abstract

Supplementary Table 1 - XLSX 39K, Exome sequencing results. The table contains the raw data for Figure 2B as well as the mutation allele frequency, the prediction of protein functionality, the inclusion in the Cancer Gene Census and the protein function. Sample legend: B, DCIS right; C, DCIS left; D, NSCLC left; E, NSCLC right; F, N2(4R)

Published
2023
Full Text
View/download PDF

44. Supplementary Figures from Clinical Response to a Lapatinib-Based Therapy for a Li-Fraumeni Syndrome Patient with a Novel HER2V659E Mutation

Author

José Baselga, Joan Seoane, Maurizio Scaltriti, Paolo Nuciforo, Ludmila Prudkin, Joaquín Arribas, Javier Hernández-Losa, Judit Grueso, Leticia De Mattos-Arruda, Josep-Lluís Parra, Ginevra Caratù, Daniel Silberschmidt, Enriqueta Felip, Xose S. Puente, Ana Vivancos, and Violeta Serra

Abstract

Supplementary Figures - PDF file 585K, Supplementary Figure 1. Fluorescence in situ hybridization (FISH) of HER2. Supplementary Figure 2. EGFR and HER2 mutations identified. Supplementary Figure 3. Comparisons of allele frequencies. Supplementary Figure 4. HER2-V659E response to erlotinib and neratinib in MCF10A cells

Published
2023
Full Text
View/download PDF

45. Supplementary Figure 6 from PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

Author

José Baselga, Maurizio Scaltriti, Leif W. Ellisen, Javier Cortés, Jordi Rodón, José Pérez, Isabel T. Rubio, Orland Díez, Claudia Aura, Maria Teresa Calvo, Olga Rodríguez, Judit Grueso, Marta Guzmán, Patricia Cozar, Pilar Anton, Aleix Prat, Kristine Torres-Lockhart, Lei He, Violeta Serra, Celina García-García, and Yasir H. Ibrahim

Abstract

PDF file - 190K, ERK and ETS1 downregulate BRCA1/2 expression

Published
2023
Full Text
View/download PDF

46. Supplementary Figure 1 from Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

Author

José Baselga, Claudia Aura, José Jimenez, Ludmila Prudkin, Varenka Rodriguez, Kip A. West, Kelly L. Slocum, Alice R. Lim, Olga Rodriguez, Marta Guzman, Emmanuel Normant, Violeta Serra, and Maurizio Scaltriti

Abstract

Supplementary Figure 1 from Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

Published
2023
Full Text
View/download PDF

47. Supplementary Table 1 from PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

Author

José Baselga, Maurizio Scaltriti, Leif W. Ellisen, Javier Cortés, Jordi Rodón, José Pérez, Isabel T. Rubio, Orland Díez, Claudia Aura, Maria Teresa Calvo, Olga Rodríguez, Judit Grueso, Marta Guzmán, Patricia Cozar, Pilar Anton, Aleix Prat, Kristine Torres-Lockhart, Lei He, Violeta Serra, Celina García-García, and Yasir H. Ibrahim

Abstract

PDF file - 139K, Common BRCA1 and BRCA2 promoter putative transcription factors analysis

Published
2023
Full Text
View/download PDF

48. Supplementary Table 1 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Table 1

Published
2023
Full Text
View/download PDF

49. Supplementary Figure 2 from Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

Author

José Baselga, Claudia Aura, José Jimenez, Ludmila Prudkin, Varenka Rodriguez, Kip A. West, Kelly L. Slocum, Alice R. Lim, Olga Rodriguez, Marta Guzman, Emmanuel Normant, Violeta Serra, and Maurizio Scaltriti

Abstract

Supplementary Figure 2 from Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

Published
2023
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results