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1. Data from Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity

Author

David A. Barbie, Matthew G. Oser, Ellis L. Reinherz, Scott Rodig, Robin Edwards, Evisa Gjini, Pasi A. Jänne, Kathleen Pfaff, Michael Y. Tolstorukov, Lynette M. Sholl, Fangxin Hong, Benjamin Chen, Xi-Tao Wang, Ana Lako, Eliezer M. Van Allen, Mark M. Awad, Cloud P. Paweletz, Prafulla C. Gokhale, Brendan Reardon, Hideo Watanabe, Maya Fridrikh, Aoi Akitsu, Shunsuke Kitajima, Israel Cañadas, Takahiko Murayama, Alison D. Santucci, Victor Quadros, Andrew Portell, Patrick H. Lizotte, Luke J. Taus, Michael J. Poitras, Jonathan S. Duke-Cohan, Bruce B. Reinhold, Saemi Han, Brandon Piel, Tran C. Thai, Deli Hong, Marco Campisi, Maria Saigí, Amir Vajdi, Jacquelyn O. Wolff, Erik H. Knelson, and Navin R. Mahadevan

Abstract

Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity.Significance:SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC Ihi subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection.This article is highlighted in the In This Issue feature, p. 1861

Published
2023

2. Supplementary Table S1 from Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity

Author

David A. Barbie, Matthew G. Oser, Ellis L. Reinherz, Scott Rodig, Robin Edwards, Evisa Gjini, Pasi A. Jänne, Kathleen Pfaff, Michael Y. Tolstorukov, Lynette M. Sholl, Fangxin Hong, Benjamin Chen, Xi-Tao Wang, Ana Lako, Eliezer M. Van Allen, Mark M. Awad, Cloud P. Paweletz, Prafulla C. Gokhale, Brendan Reardon, Hideo Watanabe, Maya Fridrikh, Aoi Akitsu, Shunsuke Kitajima, Israel Cañadas, Takahiko Murayama, Alison D. Santucci, Victor Quadros, Andrew Portell, Patrick H. Lizotte, Luke J. Taus, Michael J. Poitras, Jonathan S. Duke-Cohan, Bruce B. Reinhold, Saemi Han, Brandon Piel, Tran C. Thai, Deli Hong, Marco Campisi, Maria Saigí, Amir Vajdi, Jacquelyn O. Wolff, Erik H. Knelson, and Navin R. Mahadevan

Abstract

Supplementary Table S1

Published
2023

3. Supplementary Table S2 from Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity

Author

David A. Barbie, Matthew G. Oser, Ellis L. Reinherz, Scott Rodig, Robin Edwards, Evisa Gjini, Pasi A. Jänne, Kathleen Pfaff, Michael Y. Tolstorukov, Lynette M. Sholl, Fangxin Hong, Benjamin Chen, Xi-Tao Wang, Ana Lako, Eliezer M. Van Allen, Mark M. Awad, Cloud P. Paweletz, Prafulla C. Gokhale, Brendan Reardon, Hideo Watanabe, Maya Fridrikh, Aoi Akitsu, Shunsuke Kitajima, Israel Cañadas, Takahiko Murayama, Alison D. Santucci, Victor Quadros, Andrew Portell, Patrick H. Lizotte, Luke J. Taus, Michael J. Poitras, Jonathan S. Duke-Cohan, Bruce B. Reinhold, Saemi Han, Brandon Piel, Tran C. Thai, Deli Hong, Marco Campisi, Maria Saigí, Amir Vajdi, Jacquelyn O. Wolff, Erik H. Knelson, and Navin R. Mahadevan

Abstract

Supplementary Table S2

Published
2023

4. Supplementary Table S6 from Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity

Author

David A. Barbie, Matthew G. Oser, Ellis L. Reinherz, Scott Rodig, Robin Edwards, Evisa Gjini, Pasi A. Jänne, Kathleen Pfaff, Michael Y. Tolstorukov, Lynette M. Sholl, Fangxin Hong, Benjamin Chen, Xi-Tao Wang, Ana Lako, Eliezer M. Van Allen, Mark M. Awad, Cloud P. Paweletz, Prafulla C. Gokhale, Brendan Reardon, Hideo Watanabe, Maya Fridrikh, Aoi Akitsu, Shunsuke Kitajima, Israel Cañadas, Takahiko Murayama, Alison D. Santucci, Victor Quadros, Andrew Portell, Patrick H. Lizotte, Luke J. Taus, Michael J. Poitras, Jonathan S. Duke-Cohan, Bruce B. Reinhold, Saemi Han, Brandon Piel, Tran C. Thai, Deli Hong, Marco Campisi, Maria Saigí, Amir Vajdi, Jacquelyn O. Wolff, Erik H. Knelson, and Navin R. Mahadevan

Abstract

Supplementary Table S6

Published
2023

5. Supplementary Figures 1-12 from Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity

Author

David A. Barbie, Matthew G. Oser, Ellis L. Reinherz, Scott Rodig, Robin Edwards, Evisa Gjini, Pasi A. Jänne, Kathleen Pfaff, Michael Y. Tolstorukov, Lynette M. Sholl, Fangxin Hong, Benjamin Chen, Xi-Tao Wang, Ana Lako, Eliezer M. Van Allen, Mark M. Awad, Cloud P. Paweletz, Prafulla C. Gokhale, Brendan Reardon, Hideo Watanabe, Maya Fridrikh, Aoi Akitsu, Shunsuke Kitajima, Israel Cañadas, Takahiko Murayama, Alison D. Santucci, Victor Quadros, Andrew Portell, Patrick H. Lizotte, Luke J. Taus, Michael J. Poitras, Jonathan S. Duke-Cohan, Bruce B. Reinhold, Saemi Han, Brandon Piel, Tran C. Thai, Deli Hong, Marco Campisi, Maria Saigí, Amir Vajdi, Jacquelyn O. Wolff, Erik H. Knelson, and Navin R. Mahadevan

Abstract

Supplementary Figures 1-12

Published
2023

6. Supplementary Table S4 from Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity

Author

David A. Barbie, Matthew G. Oser, Ellis L. Reinherz, Scott Rodig, Robin Edwards, Evisa Gjini, Pasi A. Jänne, Kathleen Pfaff, Michael Y. Tolstorukov, Lynette M. Sholl, Fangxin Hong, Benjamin Chen, Xi-Tao Wang, Ana Lako, Eliezer M. Van Allen, Mark M. Awad, Cloud P. Paweletz, Prafulla C. Gokhale, Brendan Reardon, Hideo Watanabe, Maya Fridrikh, Aoi Akitsu, Shunsuke Kitajima, Israel Cañadas, Takahiko Murayama, Alison D. Santucci, Victor Quadros, Andrew Portell, Patrick H. Lizotte, Luke J. Taus, Michael J. Poitras, Jonathan S. Duke-Cohan, Bruce B. Reinhold, Saemi Han, Brandon Piel, Tran C. Thai, Deli Hong, Marco Campisi, Maria Saigí, Amir Vajdi, Jacquelyn O. Wolff, Erik H. Knelson, and Navin R. Mahadevan

Abstract

Supplementary Table S4

Published
2023

7. Supplementary Table S5 from Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity

Author

David A. Barbie, Matthew G. Oser, Ellis L. Reinherz, Scott Rodig, Robin Edwards, Evisa Gjini, Pasi A. Jänne, Kathleen Pfaff, Michael Y. Tolstorukov, Lynette M. Sholl, Fangxin Hong, Benjamin Chen, Xi-Tao Wang, Ana Lako, Eliezer M. Van Allen, Mark M. Awad, Cloud P. Paweletz, Prafulla C. Gokhale, Brendan Reardon, Hideo Watanabe, Maya Fridrikh, Aoi Akitsu, Shunsuke Kitajima, Israel Cañadas, Takahiko Murayama, Alison D. Santucci, Victor Quadros, Andrew Portell, Patrick H. Lizotte, Luke J. Taus, Michael J. Poitras, Jonathan S. Duke-Cohan, Bruce B. Reinhold, Saemi Han, Brandon Piel, Tran C. Thai, Deli Hong, Marco Campisi, Maria Saigí, Amir Vajdi, Jacquelyn O. Wolff, Erik H. Knelson, and Navin R. Mahadevan

Abstract

Supplementary Table S5

Published
2023

8. Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of

Author

Pınar Özden, Eser, Raymond M, Paranal, Jieun, Son, Elena, Ivanova, Yanan, Kuang, Heidi M, Haikala, Ciric, To, Jeffrey J, Okoro, Kshiti H, Dholakia, Jihyun, Choi, Yoonji, Eum, Atsuko, Ogino, Pavlos, Missios, Dalia, Ercan, Man, Xu, Michael J, Poitras, Stephen, Wang, Kenneth, Ngo, Michael, Dills, Masahiko, Yanagita, Timothy, Lopez, Mika, Lin, Jeanelle, Tsai, Nicolas, Floch, Emily S, Chambers, Jennifer, Heng, Rana, Anjum, Alison D, Santucci, Kesi, Michael, Alwin G, Schuller, Darren, Cross, Paul D, Smith, Geoffrey R, Oxnard, David A, Barbie, Lynette M, Sholl, Magda, Bahcall, Sangeetha, Palakurthi, Prafulla C, Gokhale, Cloud P, Paweletz, George Q, Daley, and Pasi A, Jänne

Subjects
ErbB Receptors, Lung Neoplasms, Drug Resistance, Neoplasm, Cell Line, Tumor, Mutation, Humans, Protein Kinase Inhibitors, Article
Abstract

The clinical efficacy of epidermal growth factor receptor (EGFR)–targeted therapy in EGFR-mutant non–small cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR inhibitor resistance occurs through amplification of the human growth factor receptor (MET) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent EGFR mutation and MET amplification are historically thought to be codependent on the activation of both oncogenes. Hence, patients whose tumors harbor both alterations are commonly treated with a combination of EGFR and MET tyrosine kinase inhibitors (TKIs). Here, we identify and characterize six patient-derived models of EGFR-mutant, MET-amplified lung cancer that have switched oncogene dependence to rely exclusively on MET activation for survival. We demonstrate in this MET-driven subset of EGFR TKI-refractory cancers that canonical EGFR downstream signaling was governed by MET, even in the presence of sustained mutant EGFR expression and activation. In these models, combined EGFR and MET inhibition did not result in greater efficacy in vitro or in vivo compared to single-agent MET inhibition. We further identified a reduced EGFR:MET mRNA expression stoichiometry as associated with MET oncogene dependence and single-agent MET TKI sensitivity. Tumors from 10 of 11 EGFR inhibitor–resistant EGFR-mutant, MET-amplified patients also exhibited a reduced EGFR:MET mRNA ratio. Our findings reveal that a subset of EGFR-mutant, MET-amplified lung cancers develop dependence on MET activation alone, suggesting that such patients could be treated with a single-agent MET TKI rather than the current standard-of-care EGFR and MET inhibitor combination regimens.

Published
2021

9. Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of EGFR -mutant lung cancer

Author

Emily S. Chambers, Alwin Schuller, Stephen Wang, Dalia Ercan, Mika Lin, Pınar Özden Eser, Raymond M. Paranal, Nicolas Floc'h, Sangeetha Palakurthi, Alison D. Santucci, Jeffrey J. Okoro, Geoffrey R. Oxnard, Man Xu, Kenneth H. Ngo, Jeanelle Tsai, Ciric To, Lynette M. Sholl, George Q. Daley, Michael Dills, Pavlos Missios, Kesi Michael, Paul D. Smith, Yoonji Eum, Magda Bahcall, Yanan Kuang, David A. Barbie, Masahiko Yanagita, Jennifer C. Heng, Rana Anjum, Prafulla C. Gokhale, Elena Ivanova, Jieun Son, Kshiti Dholakia, Heidi M. Haikala, Darren Cross, Jihyun Choi, Michael J. Poitras, Pasi A. Jänne, Timothy Lopez, Cloud P. Paweletz, and Atsuko Ogino

Subjects
biology, business.industry, Extramural, Mutant, General Medicine, Drug resistance, medicine.disease, Cancer research, biology.protein, Medicine, Single agent, Clinical efficacy, Non small cell, Epidermal growth factor receptor, business, Lung cancer
Abstract

A subset of drug-resistant EGFR -mutant MET -amplified lung cancer switches oncogenic dependence to MET and is treatable with MET inhibitor monotherapy.

Published
2021

10. Matrix metalloproteinase signals following neurotrauma are right on cue

Author

Alpa Trivedi, Jonathan M. Levine, Alison D. Santucci, Linda J. Noble-Haeusslein, Linda L. Phillips, and Thomas M. Reeves

Subjects
Context (language use), Hippocampal formation, Hippocampus, Glial scar, Synapse, Lesion, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Animals, Humans, Molecular Biology, Spinal Cord Injuries, Neuroinflammation, Pharmacology, 0303 health sciences, business.industry, 030302 biochemistry & molecular biology, Optic Nerve, Cell Biology, Spinal cord, Olfactory Bulb, Axons, Matrix Metalloproteinases, medicine.anatomical_structure, Blood-Brain Barrier, Synapses, Optic nerve, Molecular Medicine, medicine.symptom, business, Neuroscience
Abstract

Neurotrauma, a term referencing both traumatic brain and spinal cord injuries, is unique to neurodegeneration in that onset is clearly defined. From the perspective of matrix metalloproteinases (MMPs), there is opportunity to define their temporal participation in injury and recovery beginning at the level of the synapse. Here we examine the diverse roles of MMPs in the context of targeted insults (optic nerve lesion and hippocampal and olfactory bulb deafferentation), and clinically relevant focal models of traumatic brain and spinal cord injuries. Time-specific MMP postinjury signaling is critical to synaptic recovery after focal axonal injuries; members of the MMP family exhibit a signature temporal profile corresponding to axonal degeneration and regrowth, where they direct postinjury reorganization and synaptic stabilization. In both traumatic brain and spinal cord injuries, MMPs mediate early secondary pathogenesis including disruption of the blood-brain barrier, creating an environment that may be hostile to recovery. They are also critical players in wound healing including angiogenesis and the formation of an inhibitory glial scar. Experimental strategies to reduce their activity in the acute phase result in long-term neurological recovery after neurotrauma and have led to the first clinical trial in spinal cord injured pet dogs.

Published
2019

11. FP14.07 Combination Osimertinib plus Selpercatinib for EGFR-mutant Non-Small Cell Lung Cancer (NSCLC) with Acquired RET fusions

Author

Jonathan H. Goldman, Alison D. Santucci, Julia K Rotow, Jyoti D. Patel, L. Silva, A. Drilon, Jennifer Kherani, H. Nechustan, R. Tupper, M. Hanley, Helena Alexandra Yu, Geoffrey R. Oxnard, Matthias Scheffler, Mark M. Awad, and Sarah E. Clifford

Subjects
Pulmonary and Respiratory Medicine, Oncology, business.industry, Mutant, Cancer research, Medicine, non-small cell lung cancer (NSCLC), Osimertinib, business, medicine.disease
Published
2021

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