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The Mechanism of Action (MoA) of a drug is generally represented as a small, non-tissue-specific repertoire of high-affinity binding targets. Yet, drug activity and polypharmacology are increasingly associated with a broad range of off-target and tissue-specific effector proteins. To address this challenge, we have leveraged a microfluidics-based Plate-Seq technology to survey drug perturbational profiles representing >700 FDA-approved and experimental oncology drugs, in cell lines selected as high-fidelity models of 23 aggressive tumor subtypes. Built on this dataset, we implemented an efficient computational framework to define a tissue-specific protein activity landscape of these drugs and reported almost 50 million differential protein activities derived from drug perturbations vs. vehicle controls. These analyses revealed thousands of highly reproducible and novel, drug-mediated modulation of tissue-specific targets, leading to generation of a proteome-wide drug functional network, characterization of MoA-related drug clusters and off-target effects, dramatical expansion of druggable human proteome, and identification and experimental validation of novel, tissue-specific inhibitors of undruggable oncoproteins, most never reported before. The drug perturbation profile resource described here represents the first, large-scale, whole-genome-wide, RNA-Seq based dataset assembled to date, with the proposed framework, which is easily extended to elucidating the MoA of novel small-molecule libraries, facilitates mechanistic exploration of drug functions, supports systematic and quantitative approaches to precision oncology, and serves as a rich data foundation for drug discovery.

Homologous recombination repair (HRR) pathway deficiency opens multiple therapeutic avenues within pancreatic cancer. Patients with HRR deficiency-associated gene mutations such as BRCA1, BRCA2, and PALB2 are more susceptible to platinum-based chemotherapies and in those with somatic BRCA mutations, PARP inhibitor therapy prolongs progression-free survival. The case discussed herein illustrates the therapeutic opportunities offered through the identification of HRR deficiency in pancreatic cancer, as well as the challenges associated with treatment and prevention of central nervous system metastases in long-term survivors of pancreatic cancer., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach., Methods: In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2- MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%., Results: Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo., Conclusion: In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2- MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.

Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study., Significance: Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials. This article is highlighted in the In This Issue feature, p. 1275., (©2023 American Association for Cancer Research.)

Genomic alterations in the receptor tyrosine kinase RET represent actionable driver events in several cancer types. Activation of the kinase domain by point mutations represents a pathognomonic event in medullary thyroid cancer, while RET fusions are critical driver events in a sizable subset of differentiated thyroid cancer and a smaller percentage of lung cancer. Early trials with multi-kinase inhibitors yielded modest improvement in outcomes for RET-driven cancers. In recent years, highly selective RET inhibitors entered clinical trials and demonstrated remarkable response rates, resulting in accelerated approval for selpercatinib and pralsetinib in 2020. An important mechanism of eventual resistance to RET inhibitors is the emergence of secondary drug resistance mutations, particularly in the solvent front, and several promising compounds are in development to overcome these mutations. Mechanisms of acquired resistance that bypass RET signaling altogether have also been discovered, suggesting that combinatorial drug strategies may be necessary for some patients., Competing Interests: Conflict of interest statement The authors have no conflicts of interest to disclose., (Published by Elsevier B.V.)

Background: Malignant rhabdoid tumors (MRTs) and Wilms' tumors (WTs) are rare and aggressive renal tumors of infants and young children comprising ∼5% of all pediatric cancers. MRTs are among the most genomically stable cancers, and although WTs are genomically heterogeneous, both generally lack therapeutically targetable genetic mutations., Methods: Comparative protein activity analysis of MRTs (n = 68) and WTs (n = 132) across TCGA and TARGET cohorts, using metaVIPER, revealed elevated exportin 1 (XPO1) inferred activity. In vitro studies were performed on a panel of MRT and WT cell lines to evaluate effects on proliferation and cell-cycle progression following treatment with the selective XPO1 inhibitor selinexor. In vivo anti-tumor activity was assessed in patient-derived xenograft (PDX) models of MRTs and WTs., Findings: metaVIPER analysis identified markedly aberrant activation of XPO1 in MRTs and WTs compared with other tumor types. All MRT and most WT cell lines demonstrated baseline, aberrant XPO1 activity with in vitro sensitivity to selinexor via cell-cycle arrest and induction of apoptosis. In vivo, XPO1 inhibitors significantly abrogated tumor growth in PDX models, inducing effective disease control with sustained treatment. Corroborating human relevance, we present a case report of a child with multiply relapsed WTs with prolonged disease control on selinexor., Conclusions: We report on a novel systems-biology-based comparative framework to identify non-genetically encoded vulnerabilities in genomically quiescent pediatric cancers. These results have provided preclinical rationale for investigation of XPO1 inhibitors in an upcoming investigator-initiated clinical trial of selinexor in children with MRTs and WTs and offer opportunities for exploration of inferred XPO1 activity as a potential predictive biomarker for response., Funding: This work was funded by CureSearch for Children's Cancer, Alan B. Slifka Foundation, NIH (U01 CA217858, S10 OD012351, and S10 OD021764), Michael's Miracle Cure, Hyundai Hope on Wheels, Cannonball Kids Cancer, Conquer Cancer the ASCO Foundation, Cycle for Survival, Paulie Strong Foundation, and the Grayson Fund., Competing Interests: Declaration of interests A.C. is co-founder, equity holder, and consultant of DarwinHealth, Inc., which has licensed intellectual property (IP) related to the VIPER algorithms from Columbia University. Columbia University is an equity holder in DarwinHealth, Inc. A.L.K. is on the Scientific Advisory Board of Emendo Biotherapeutics, Karyopharm Therapeutics, Imago BioSciences, and DarwinHealth, is co-founder and on the board of directors of Isabl Technologies, and has equity interest in Imago BioSciences, Emendo Biotherapeutics, and Isabl Technologies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Disclosure The authors have no conflicts of interest to disclose.

The NTRK genes encode the tropomyosin-related receptor tyrosine kinases TrkA, TrkB and TrkC. TRK receptors regulate the proliferation, differentiation, and survival of many neuronal and non-neuronal glial cells during embryogenesis, thus playing a critical role in synaptic plasticity and the development of nociceptive pathways. Recurrent genomic alterations in NTRK genes, typically fusions involving the 3' region encoding the kinase domain juxtaposed to 5' sequences from numerous partner genes, occur at a low frequency in a wide diversity of adult and pediatric cancers. The contributions of the resulting constitutively activated kinase to oncogenesis and cancer progression are being elucidated. Larotrectinib and entrectinib are potent first-generation TRK inhibitors with IC 50 values in the nanomolar range across cancer cell lines harboring NTRK fusions. Larotrectinib is highly selective for TRK receptors, whereas entrectinib also potently inhibits ROS1 and ALK. Clinical trials of both drugs demonstrated significant and durable responses in patients with tumors harboring NTRK alterations, leading to first of its kind cancer agnostic FDA approvals in the United States for drugs targeting a genomic alteration. Unfortunately, acquired resistance inevitably develops. The second-generation TRK inhibitors selitrectinib and repotrectinib are designed to overcome known mechanisms of resistance., (Published by Elsevier B.V.)

Purpose: Both gain-of-function enhancer of zeste homolog 2 (EZH2) mutations and inactivating histone acetyltransferases mutations, such as CREBBP and EP300, have been implicated in the pathogenesis of germinal center (GC)-derived lymphomas. We hypothesized that direct inhibition of EZH2 and histone deacetyltransferase (HDAC) would be synergistic in GC-derived lymphomas., Experimental Design: Lymphoma cell lines ( n = 21) were exposed to GSK126, an EZH2 inhibitor, and romidepsin, a pan-HDAC inhibitor. Synergy was assessed by excess over bliss. Western blot, mass spectrometry, and coimmunoprecipitation were performed. A SU-DHL-10 xenograft model was utilized to validate in vitro findings. Pretreatment RNA-sequencing of cell lines was performed. MetaVIPER analysis was used to infer protein activity., Results: Exposure to GSK126 and romidepsin demonstrated potent synergy in lymphoma cell lines with EZH2 dysregulation. Combination of romidepsin with other EZH2 inhibitors also demonstrated synergy suggesting a class effect of EZH2 inhibition with romidepsin. Dual inhibition of EZH2 and HDAC led to modulation of acetylation and methylation of H3K27. The synergistic effects of the combination were due to disruption of the PRC2 complex secondary to acetylation of RbAP 46/48. A common basal gene signature was shared among synergistic lymphoma cell lines and was characterized by upregulation in chromatin remodeling genes and transcriptional regulators. This finding was supported by metaVIPER analysis which also revealed that HDAC 1/2 and DNA methyltransferase were associated with EZH2 activation., Conclusions: Inhibition of EZH2 and HDAC is synergistic and leads to the dissociation of PRC2 complex. Our findings support the clinical translation of the combination of EZH2 and HDAC inhibition in EZH2 dysregulated lymphomas., (©2019 American Association for Cancer Research.)

The phosphatidylinositol-3 kinase (PI3K)-AKT pathway is one of the most commonly dysregulated pathways in all of cancer, with somatic mutations, copy number alterations, aberrant epigenetic regulation and increased expression in a number of cancers. The carefully maintained homeostatic balance of cell division and growth on one hand, and programmed cell death on the other, is universally disturbed in tumorigenesis, and downstream effectors of the PI3K-AKT pathway play an important role in this disturbance. With a wide array of downstream effectors involved in cell survival and proliferation, the well-characterized direct interactions of AKT make it a highly attractive yet elusive target for cancer therapy. Here, we review the salient features of this pathway, evidence of its role in promoting tumorigenesis and recent progress in the development of therapeutic agents that target AKT., (© 2016 The British Pharmacological Society.)