We performed molecular profiling of the largest series to date of crizotinib- and lorlatinib-resistant biopsies, finding that ROS1 kinase domain mutations mediate resistance in one third to one half of cases, respectively. Recurrent resistance mutations in ROS1 included G2032R and less well-characterized L2086F. In Ba/F3 models, type I inhibitors, including crizotinib, entrectinib, and lorlatinib, were unable to overcome ROS1L2086F, whereas type II inhibitor, cabozantinib, maintained potency. We additionally detected MET and RAS-MAPK alterations in resistant specimens. Our study highlights the importance of developing novel ROS1 inhibitors with potency against recurrent ROS1 resistance mutations and may inform sequential treatment strategies in ROS1+ lung cancer. ROS1 mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms. READ ARTICLE
Cancer Mechanisms and Therapy DOI:10.1158/1078-0432.CCR-21-0032
Authors: Jessica J. Lin, Noura J. Choudhury, Satoshi Yoda, Viola W. Zhu, Ted W. Johnson, Ramin Sakhtemani, Ibiayi Dagogo-Jack, Subba R. Digumarthy, Charlotte Lee, Andrew Do, Jennifer Peterson, Kylie Prutisto-Chang, Wafa Malik, Harper G. Hubbeling, Adam Langenbucher, Adam J. Schoenfeld, Christina J. Falcon, Jennifer S. Temel, Lecia V. Sequist, Beow Y. Yeap, Jochen K. Lennerz, Alice T. Shaw, Michael S. Lawrence, Sai-Hong Ignatius Ou, Aaron N. Hata, Alexander Drilon, Justin F. Gainor
