@article{916a35d1abfa4831a26bbb1adb09cced,
title = "MYC Promotes Tyrosine Kinase Inhibitor Resistance in ROS1-Fusion-Positive Lung Cancer",
abstract = "Targeted therapy of ROS1-fusion-driven non-small cell lung cancer (NSCLC) has achieved notable clinical success. Despite this, resistance to therapy inevitably poses a significant challenge. MYC amplification was present in ~19% of lorlatinib-resistant ROS1-driven NSCLC. We hypothesized that MYC overexpression drives ROS1-TKI resistance. Using complementary approaches in multiple models, including a MYC-amplified patient-derived cell line and xenograft (LUAD-0006), we established that MYC overexpression induces broad ROS1-TKI resistance. Pharmacologic inhibition of ROS1 combined with MYC knockdown were essential to completely suppress LUAD-0006 cell proliferation compared with either treatment alone. We interrogated cellular signaling in ROS1-TKIresistant LUAD-0006 and discovered significant differential regulation of targets associated with cell cycle, apoptosis, and mitochondrial function. Combinatorial treatment of mitochondrial inhibitors with crizotinib revealed inhibitory synergism, suggesting increased reliance on glutamine metabolism and fatty-acid synthesis in chronic ROS1-TKI treated LUAD-0006 cells. In vitro experiments further revealed that CDK4/6 and BET bromodomain inhibitors effectively mitigate ROS1-TKI resistance in MYCoverexpressing cells. Notably, in vivo studies demonstrate that tumor control may be regained by combining ROS1-TKI and CDK4/6 inhibition. Our results contribute to the broader understanding of ROS1-TKI resistance in NSCLC. Implications: This study functionally characterizes MYC overexpression as a novel form of therapeutic resistance to ROS1 tyrosine kinase inhibitors in non-small cell lung cancer and proposes rational combination treatment strategies.",
author = "Iyer, {Sudarshan R.} and Igor Odintsov and Schoenfeld, {Adam J.} and Evan Siau and Mattar, {Marissa S.} and {de Stanchina}, Elisa and Inna Khodos and Alexander Drilon and Riely, {Gregory J.} and Marc Ladanyi and Romel Somwar and Davare, {Monika A.}",
note = "Funding Information: We would like to thank the following colleagues: Drs. Steve Kurtz and Jeffrey Tyner for contributing the small-molecule inhibitor panel; Drs. Jacob Henderson and Sunil Joshi for resource sharing; Karina Ray, Dr. Suzanne Fei, Dr. Lina Gao, and Dr. Jessica Minnier for bioinformatics support; and Dr. Marilyne Labrie for help with RPPA analysis. This project was supported with funding from the NCI of the NIH (NRSA: F30CA247253, R01CA233495), OHSU Doernbecher Children's Hospital Foundation, and Memorial Sloan Kettering Cancer Center Support Grant (NCI of the NIH P30 CA008748). Funding Information: We would like to thank the following colleagues: Drs. Steve Kurtz and Jeffrey Tyner for contributing the small-molecule inhibitor panel; Drs. Jacob Henderson and Sunil Joshi for resource sharing; Karina Ray, Dr. Suzanne Fei, Dr. Lina Gao, and Dr. Jessica Minnier for bioinformatics support; and Dr. Marilyne Labrie for help with RPPA analysis. This project was supported with funding from the NCI of the NIH (NRSA: F30CA247253, R01CA233495), OHSU Doernbecher Children{\textquoteright}s Hospital Foundation, and Memorial Sloan Kettering Cancer Center Support Grant (NCI of the NIH P30 CA008748). Funding Information: selpercatinib osimertinib pending; and royalties: Wolters Kluwer; other: Merck, Puma, Merus, Boehringer Ingelheim, CME honoraria: Medscape, OncLive, Peer-Voice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, AXIS, EPG Health, and JNCC/Harborside. G.J. Riely reports grants from Pfizer, Novartis, Merck, Roche, Mirati, and Takeda outside the submitted work. R. Somwar reports grants and nonfinancial support from Merus, Helsinn Healthcare, Loxo Oncology, and Elevation Oncology outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research",
year = "2022",
month = may,
doi = "10.1158/1541-7786.MCR-22-0025",
language = "English (US)",
volume = "20",
pages = "722--734",
journal = "Cell Growth and Differentiation",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "5",
}