MAPK pathway alterations correlate with poor survival and drive resistance to therapy in patients with lung cancers driven by ROS1 fusions Journal Article


Authors: Sato, H.; Schoenfeld, A. J.; Siau, E.; Lu, Y. C.; Tai, H.; Suzawa, K.; Kubota, D.; Lui, A. J. W.; Qeriqi, B.; Mattar, M.; Offin, M.; Sakaguchi, M.; Toyooka, S.; Drilon, A.; Rosen, N. X.; Kris, M. G.; Solit, D.; De Stanchina, E.; Davare, M. A.; Riely, G. J.; Ladanyi, M.; Somwar, R.
Article Title: MAPK pathway alterations correlate with poor survival and drive resistance to therapy in patients with lung cancers driven by ROS1 fusions
Abstract: PURPOSE: ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes. EXPERIMENTAL DESIGN: ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines. RESULTS: Eight of the 75 patients with a ROS1 fusion had a concurrent MAPK pathway alteration and this correlated with shorter overall survival. In addition, the induction of ROS1 fusions stimulated activation of MEK/ERK signaling with minimal effects on AKT signaling, suggesting the importance of the MAPK pathway in driving ROS1 fusion-positive cancers. Of 8 patients, 2 patients harbored novel in-frame deletions in MEK1 (MEK1delE41_L54) and MEKK1 (MEKK1delH907_C916) that were acquired after ROS1 TKIs, and 2 patients harbored NF1 loss-of-function mutations. Expression of MEK1del or MEKK1del, and knockdown of NF1 in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del. CONCLUSIONS: We demonstrate that downstream activation of the MAPK pathway can mediate of innate acquired resistance to ROS1 TKIs and that patients harboring ROS1 fusion and concurrent downstream MAPK pathway alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations. ©2020 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 26
Issue: 12
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2020-06-15
Start Page: 2932
End Page: 2945
Language: English
DOI: 10.1158/1078-0432.Ccr-19-3321
PUBMED: 32122926
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 1 July 2020 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    381 Rosen
  2. David Solit
    553 Solit
  3. Marc Ladanyi
    1050 Ladanyi
  4. Gregory J Riely
    420 Riely
  5. Romel Somwar
    55 Somwar
  6. Mark Kris
    716 Kris
  7. Alexander Edward Drilon
    251 Drilon
  8. Marissa   Mattar
    19 Mattar
  9. Michael David Offin
    46 Offin
  10. Evan Gelenn Dio Siau
    4 Siau
  11. Ken Suzawa
    9 Suzawa
  12. Besnik Qeriqi
    8 Qeriqi
  13. Hui-Chun Tai
    3 Tai
  14. Yue Christine Lu
    4 Lu
  15. Daisuke Kubota
    5 Kubota
  16. Jo Weng Allan Lui
    2 Lui
  17. Hiroki Sato
    5 Sato