On-target resistance to next-generation kinase inhibitors, drugs specifically designed to maintain potency in the setting of kinase domain mutations, remains poorly characterized. Having identified that xDFG (TRKA G667) mutations confer second-generation TRK inhibitor resistance in patients with TRK fusion-positive cancers, we used computational modeling and biochemical assays to study how these affect drug binding. We found that xDFG mutations stabilize the inactive kinase conformation, hampering the binding of type I second-generation TRK inhibitors, while increasing the affinity for type II multikinase inhibitors. Type II drugs consistently inhibit the growth and TRK-mediated signaling of isogenic and patient-derived models harboring xDFG mutations. Collectively these data demonstrate that TRK xDFG substitutions trigger conformational changes that favor type II binding mechanisms. Given prior identification of paralogous xDFG resistance mutations in other oncogene addicted cancers, these findings provide insight into rational drug design to address these recalcitrant resistant alterations by leveraging inhibitor class affinity switching.
Keywords: drug resistance, tyrosine kinase inhibitors, cancer, signaling
Cocco, Emiliano and Lee, Ji Eun and Kannan, Srinivasaraghavan and Schram, Alison M. and Won, Helen and Shifman, Sophie and Kulick, Amanda and Baldino, Laura and Toska, Eneda and Arena, Sabrina and Mussolin, Benedetta and Kannan, Ram and Vasan, Neil and Gorelick, Alexander N. and Berger, Michael F. and Liao, Yi and Rix, Uwe and Bardelli, Alberto and Hechtman, Jacklyn and de Stanchina, Elisa and Hyman, David M. and Verma, Chandra and Ventura, Andrea and Drilon, Alexander and Scaltriti, Maurizio, TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors (December 11, 2019). Available at SSRN: https://ssrn.com/abstract=3501844 or http://dx.doi.org/10.2139/ssrn.3501844
This version of the paper has not been formally peer reviewed.
Subscribe to this free journal for more curated articles on this topic
FOLLOWERS
20
PAPERS
9,210
Feedback
Feedback to SSRN
If you need immediate assistance, call 877-SSRNHelp (877 777 6435) in the United States, or +1 212 448 2500 outside of the United States, 8:30AM to 6:00PM U.S. Eastern, Monday - Friday.