Identifying the determinants of sensitivity and resistance to small molecule kinase inhibitors

Kinase inhibitors are an intensively studied class of therapeutics with many remaining unknowns – LSP investigators use them to develop new approaches for identifying targets and to study the factors determining drug resistance and sensitivity.

Inhibitors of the roughly 540 human protein and lipid kinases are the most intensively developed and studied class of therapeutic drugs. Kinase inhibitors such as imatinib (for treatment of chronic myeloid leukemia), vemurafenib (for treatment of BRAF-mutant melanoma), and erlotinib (for treatment of EGFR-mutant lung cancer) were the first breakthrough  “targeted” drugs invented for genetically defined cancers. Kinase inhibitors are also important in the treatment of inflammatory diseases. However, a primary limitation in the use of these drugs is the frequent development of resistance, which involves both a short-term adaptive resistance and genetically determined long-term resistance. Resistance mechanisms involve many of the homeostatic processes that allow cells to survive and proliferate in the presence of internal and external stress and are, therefore, interesting in their own right. By studying precisely how drug resistance arises in cell lines, animal models, and humans, we hope to prevent its emergence using newly developed drugs or combination therapies. This project is ideal for cancer biologists and oncologists interested in fundamentally improving our approach to small molecule therapy and increasing the durability of therapeutic responses. Clinical trials are underway making use of some of the insights arising from this project.