Small molecule cancer therapies

There have been enormous efforts dedicated to developing kinase inhibitors as a means of treating cancer. However, regardless of the molecular target (activated BRAF or EGFR, for example), this approach has been hindered due to the rapid emergence of drug resistance in nearly all cases. Here we report “Integrator Therapy”, a cancer treatment using a small molecule, INTi, to inhibit Integrator. INTi treatment in variety of cancer cell lines leads to increased expression of immediate early genes (IEGs), loss of responsiveness to growth factors, induction of DNA damage response and loss of cellular proliferation. INTi treatment of melanoma patient-derived tumor xenograft (PDX) with BRAF (V600E) or NRAS mutations alleviate tumor growth in vivo. Remarkably, INTi treatment overcomes resistance to BRAF targeted therapy in human melanoma cell lines and PDX models in vivo, pointing to Integrator therapy as a complementary treatment.