Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer

Kurtis D. Davies, Sakshi Mahale, David P. Astling, Dara L. Aisner, Anh T. Le, Trista K. Hinz, Aria Vaishnavi, Paul A. Bunn, Lynn E. Heasley, Aik Choon Tan, D. Ross Camidge, Marileila Varella-Garcia, Robert C. Doebele

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69 Citations (Scopus)

Abstract

The targeting of oncogenic 'driver' kinases with small molecule inhibitors has proven to be a highly effective therapeutic strategy in selected non-small cell lung cancer (NSCLC) patients. However, acquired resistance to targeted therapies invariably arises and is a major limitation to patient care. ROS1 fusion proteins are a recently described class of oncogenic driver, and NSCLC patients that express these fusions generally respond well to ROS1-targeted therapy. In this study, we sought to determine mechanisms of acquired resistance to ROS1 inhibition. To accomplish this, we analyzed tumor samples from a patient who initially responded to the ROS1 inhibitor crizotinib but eventually developed acquired resistance. In addition, we generated a ROS1 inhibition-resistant derivative of the initially sensitive NSCLC cell line HCC78. Previously described mechanisms of acquired resistance to tyrosine kinase inhibitors including target kinase-domain mutation, target copy number gain, epithelial-mesenchymal transition, and conversion to small cell lung cancer histology were found to not underlie resistance in the patient sample or resistant cell line. However, we did observe a switch in the control of growth and survival signaling pathways from ROS1 to EGFR in the resistant cell line. As a result of this switch, ROS1 inhibition-resistant HCC78 cells became sensitive to EGFR inhibition, an effect that was enhanced by co-treatment with a ROS1 inhibitor. Our results suggest that co-inhibition of ROS1 and EGFR may be an effective strategy to combat resistance to targeted therapy in some ROS1 fusion-positive NSCLC patients.

Original languageEnglish
Article numbere82236
JournalPloS one
Volume8
Issue number12
DOIs
Publication statusPublished - 2013 Dec 13

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Davies, K. D., Mahale, S., Astling, D. P., Aisner, D. L., Le, A. T., Hinz, T. K., Vaishnavi, A., Bunn, P. A., Heasley, L. E., Tan, A. C., Camidge, D. R., Varella-Garcia, M., & Doebele, R. C. (2013). Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer. PloS one, 8(12), [e82236]. https://doi.org/10.1371/journal.pone.0082236