Activation of RAS family members confers resistance to ROS1 targeting drugs.

Marilisa Cargnelutti,Jorge Vialard,Simona Corso,Rafal Dziadziuszko,Marileila Varella-Garcia,Silvia Giordano,Laurence Mévellec,Paolo M Comoglio,Robert C Doebele,Dara L Aisner,Margherita Pergolizzi

doi:10.18632/oncotarget.3311

Abstract

The ROS1 tyrosine kinase is activated in lung cancer as a consequence of chromosomal rearrangement. Although high response rates and disease control have been observed in lung cancer patients bearing rearranged ROS1 tumors (ROS1+) treated with the kinase inhibitor crizotinib, many of these patients eventually relapse.To identify mechanisms of resistance to ROS1 inhibitors we generated resistant cells from HCC78 lung cancer cells bearing the SLC34A2-ROS1 rearrangement. We found that activation of the RAS pathway in the HCC78 cell model, due to either KRAS/NRAS mutations or to KRAS amplification, rendered the cells resistant to ROS1 inhibition. These cells were cross-resistant to different ROS1 inhibitors, but sensitive to inhibitors of the RAS signaling pathway. Interestingly, we identified focal KRAS amplification in a biopsy of a tumor from a patient that had become resistant to crizotinib treatment.Altogether our data suggest that the activation of members of the RAS family can confer resistance to ROS1 inhibitors. This has important clinical implications as: (i) RAS genetic alterations in ROS1+ primary tumors are likely negative predictors of efficacy for targeted drugs and (ii) this kind of resistance is unlikely to be overcome by the use of more specific or more potent ROS1 targeting drugs.

Highlights

Lung cancer is the leading cause of cancer related death, with about 1.6 million cases diagnosed yearly worldwide, resulting in 1.4 million deaths [1]
In vitro studies confirmed that the rearranged ROS1 kinase is constitutively active and that it behaves as a tumor driver, since cells are addicted to its continuous activation
Preclinical studies demonstrating that the FDA-approved ALK inhibitor, crizotinib, inhibits ROS1 provided rationale for its use in treatment of ROS1+ nonsmall-cell lung cancers (NSCLC) patients [28]

Summary

Introduction

Lung cancer is the leading cause of cancer related death, with about 1.6 million cases diagnosed yearly worldwide, resulting in 1.4 million deaths [1]. The identification of oncogenic mutations in receptor tyrosine kinases (RTK) such as EGFR [3, 4] and, less commonly, rearrangement of ALK, RET and ROS1 in www.impactjournals.com/oncotarget adenocarcinoma [5], has influenced treatment strategies by providing rationale for treatment with tyrosine kinase inhibitors (TKI) directed against these targets. This has contributed to the approval of erlotinib for mutated EGFR tumors [6, 7] and crizotinib for ALK rearranged neoplasms [8]

Methods

Results

Conclusion