Abstract
The advent of genomics has led to the identification of specific “driver” mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions. These specific inhibitors have been a clinical success, and often significantly prolong the lives of individuals with cancer. Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Here, we review the major mechanisms by which a cancer cell can evade targeted therapy, focusing on mechanisms of resistance to kinase inhibitors in lung cancer. We discuss the promising concept of rational upfront polytherapy in lung cancer, which involves concurrently targeting multiple proteins in critical signaling pathways in a cancer cell to prevent or delay resistance.
Highlights
The advent of genomics has led to the identification of specific “driver” mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions
TARGETING DRIVER ONCOGENES IN LUNG ADENOCARCINOMA A significant fraction of lung adenocarcinomas harbor activatingmutations in targetable oncogenes. These include mutations in EGFR (~11%) and BRAF (~7%), and activating gene rearrangements involving ALK and ROS1 (1–2%), all of which encode protein kinases, and result in hyperactivation of downstream signaling pathways that drive cell growth, proliferation, and survival. The identification of these driver kinases has led to the clinical use of small molecule kinase inhibitors that suppress these oncoproteins—erlotinib, gefinitib, afatinib, osimertinib for mutant EGFR, vemurafenib and dabrafenib for mutant BRAF, and crizotinib, ceritinib, alectinib for ALK and/or ROS1 gene rearrangements.[1,2,3,4,5,6,7,8,9,10]
Small molecule kinase inhibitors bind to their target through non-covalent bonds within the ATP-binding pocket
Summary
Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma. TARGETING DRIVER ONCOGENES IN LUNG ADENOCARCINOMA A significant fraction of lung adenocarcinomas harbor activatingmutations in targetable oncogenes These include mutations in EGFR (~11%) and BRAF (~7%), and activating gene rearrangements involving ALK and ROS1 (1–2%), all of which encode protein kinases, and result in hyperactivation of downstream signaling pathways that drive cell growth, proliferation, and survival. The identification of these driver kinases has led to the clinical use of small molecule kinase inhibitors that suppress these oncoproteins—erlotinib, gefinitib, afatinib, osimertinib for mutant EGFR, vemurafenib and dabrafenib for mutant BRAF, and crizotinib, ceritinib, alectinib for ALK and/or ROS1 gene rearrangements.[1,2,3,4,5,6,7,8,9,10] These targeted drugs function as ATP-competitive inhibitors. All of these inhibitors have shown efficacy over conventional chemotherapies in patients harboring the cognate genetic driver kinase
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