We also present the crystal framework of crizotinib bound to the ROS1 kinase domain. Unlike the classic gatekeeper mutations for drug resistance that have been identified in ABL, 21 EGFR, 22 and ALK, 14 the G2032R ROS1 mutation is situated in the solvent front of the kinase domain and can be analogous to the G1202R ALK mutation determined in crizotinib-resistant ALK-rearranged lung cancers15 . Whereas the L1196M ALK gatekeeper mutant may still be sensitive to newer ALK inhibitors, such as for example CH5424802,18 we previously discovered that G1202R ALK confers high-level resistance to crizotinib and to all the next-era ALK inhibitors that were examined.15 In light of the observations, it may be necessary to identify novel compounds that target the G1202R ALK or G2032R ROS1 mutant specifically, to overcome the development of crizotinib level of resistance in these cancers.‘Am I happy? Sometimes,’ she says. ‘Always on vacation though!’.. Rafael Rosell, M.D., Teresa Moran, M.D., Cristina Queralt, B.S., Rut Porta, M.D., Felipe Cardenal, M.D., Carlos Camps, M.D., Margarita Majem, M.D., Guillermo Lopez-Vivanco, M.D., Dolores Isla, M.D., Mariano Provencio, M.D., Amelia Insa, M.D., Bartomeu Massuti, M.D., Jose Luis Gonzalez-Larriba, M.D., Luis Paz-Ares, M.D., Isabel Bover, M.D., Rosario Garcia-Campelo, M.D., Miguel Angel Moreno, M.D., Silvia Catot, M.D., Christian Rolfo, M.D., Noemi Reguart, M.D., Ramon Palmero, M.D.D., Roman Bastus, M.D., Clara Mayo, Ph.D., Jordi Bertran-Alamillo, B.S., Miguel Angel Molina, Ph.D., Jose Javier Sanchez, M.D., and Miquel Taron, Ph.D.1,2 The two proto-oncogenes which are most mutated in pulmonary adenocarcinomas are K-ras and EGFR commonly.3-7 These mutations trigger constitutive activation of the tyrosine kinase of the EGFR by destabilizing its autoinhibited conformation, which is normally maintained in the lack of ligand stimulation.