Activation of RAS family members confers resistance to ROS1 targeting drugs

// Marilisa Cargnelutti 1 , Simona Corso 1,2 , Margherita Pergolizzi 1 , Laurence Mévellec 3 , Dara L. Aisner 4 , Rafal Dziadziuszko 5 , Marileila Varella-Garcia 4,6 , Paolo M. Comoglio 1,2 , Robert C. Doebele 6 , Jorge Vialard 7 and Silvia Giordano 1,2 1 Candiolo Cancer Institute - FPO, IRCCS, Torino, Italy 2 Department of Oncology, University of Torino, Italy 3 Janssen Research & Development, Janssen-Cilag, Val-de-Reuil, France 4 Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA 5 Medical University of Gdansk, Poland 6 Department of Medicine, Division of Medical Oncology University of Colorado School of Medicine, Aurora, CO, USA 7 Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium Correspondence: Simona Corso, email: // Silvia Giordano, email: // Keywords : drug resistance, RAS, ROS1, lung cancer, targeted therapy Received : November 11, 2014 Accepted : December 29, 2014 Published : December 31, 2014 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.