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PLoS One. 2013 Dec 13;8(12):e82236. doi: 10.1371/journal.pone.0082236. eCollection 2013.

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

Author information

1
Department of Medicine, Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
2
Department of Pathology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.
3
Department of Craniofacial Biology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, United States of America.

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.

PMID:
24349229
PMCID:
PMC3862576
DOI:
10.1371/journal.pone.0082236
[Indexed for MEDLINE]
Free PMC Article
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