MYC promotes tyrosine kinase inhibitor resistance in ROS1-fusion-positive lung cancer Journal Article

   


Authors: Iyer, S. R.; Odintsov, I.; Schoenfeld, A. J.; Siau, E.; Mattar, M. S.; de Stanchina, E.; Khodos, I.; Drilon, A.; Riely, G. J.; Ladanyi, M.; Somwar, R.; Davare, M. A.
Article 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. © 2022 American Association for Cancer Research
Keywords: oncoprotein; genetics; proto-oncogene proteins; protein kinase inhibitor; carcinoma, non-small-cell lung; lung neoplasms; protein tyrosine kinase; protein kinase inhibitors; lung tumor; protein-tyrosine kinases; non small cell lung cancer; humans; human; ros1 protein, human
Journal Title: Molecular Cancer Research
Volume: 20
Issue: 5
ISSN: 1541-7786
Publisher: American Association for Cancer Research  
Date Published: 2022-05-01
Start Page: 722
End Page: 734
Language: English
DOI: 10.1158/1541-7786.Mcr-22-0025
PUBMED: 35149545
PROVIDER: scopus
PMCID: PMC9081178
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85129997274&doi=10.1158%2f1541-7786.MCR-22-0025&partnerID=40&md5=bc0ca885dddac5e7c939f36e9e5a687b
Notes: Article -- Export Date: 1 June 2022 -- Source: Scopus
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MSK Authors
  1. Marc Ladanyi
    1326 Ladanyi
  2. Gregory J Riely
    599 Riely
  3. Romel Somwar
    110 Somwar
  4. Elisa De Stanchina
    343 De Stanchina
  5. Alexander Edward Drilon
    632 Drilon
  6. Inna Khodos
    36 Khodos
  7. Marissa Mattar
    56 Mattar
  8. Evan Gelenn Dio Siau
    7 Siau
  9. Adam Jacob Schoenfeld
    131 Schoenfeld
  10. Igor Odintsov
    23 Odintsov
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