KRAS mutation as a mechanism of resistance to Alectinib in ALK rearranged NSCLC

The treatment of advanced non-small-cell lung cancer (NSCLC) has undergone a paradigm shift since the early part of this millennium. The knowledge and detection of molecular subtypes of this entity based on the phenomenon of oncogene addiction like ALK rearrangement, has led to the emergence of an era of precision and personalized medicine. Since its discovery, many molecular targets have been developed for ALK rearranged NSCLC which have rapidly transitioned from bench to bedside, with fast approvals for clinical use. This has increased the outcome in ALK rearranged patients dramatically; however the emergence of resistance to ALK TKI is inevitable and is fundamental to ongoing research and every day clinical practice. We herein report two interesting cases of ALK rearranged NSCLC who developed resistance to second generation ALK TKI, due to the development of new KRAS mutations. By far, this mechanism in the context of alectinib has not been reported in literature and this report may stimulate further studies into the same