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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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
Externally publishedYes

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ASJC Scopus subject areas

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

Cite this

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