Abstract
Mutations in the kinase and juxtamembrane domains of the MET Receptor Tyrosine Kinase are responsible for oncogenesis in various cancers and can drive resistance to MET-directed treatments. Determining the most effective inhibitor for each mutational profile is a major challenge for MET-driven cancer treatment in precision medicine. Here, we used a deep mutational scan (DMS) of ∼5,764 MET kinase domain variants to profile the growth of each mutation against a panel of 11 inhibitors that are reported to target the MET kinase domain. We validate previously identified resistance mutations, pinpoint common resistance sites across type I, type II, and type I ½ inhibitors, unveil unique resistance and sensitizing mutations for each inhibitor, and verify non-cross-resistant sensitivities for type I and type II inhibitor pairs. We augment a protein language model with biophysical and chemical features to improve the predictive performance for inhibitor-treated datasets. Together, our study demonstrates a pooled experimental pipeline for identifying resistance mutations, provides a reference dictionary for mutations that are sensitized to specific therapies, and offers insights for future drug development.
Competing Interest Statement
JSF is a consultant for, has equity in, and receives research support from Relay Therapeutics and is a consultant for Octant Bio. N.J. is a founder of Rezo Therapeutics and a shareholder of Rezo Therapeutics, Sudo Therapeutics, and type6 Therapeutics. N.J. is a SAB member of Sudo Therapeutics, type6 Therapeutic and NIBR Oncology. The Jura laboratory has received sponsored research support from Genentech, Rezo Therapeutics and type6 Therapeutics. E.A.C. is a consultant at IHP Therapeutics, Valar Labs, Tatara Therapeutics and Pear Diagnostics, reports receiving commercial research grants from Pfizer, and has stock ownership in Tatara Therapeutics, HDT Bio, Clara Health, Aqtual, and Guardant Health.
Footnotes
Response to reviews at elife. Addition of previously characterized resistance mutations figure.