Targeting RAF for Cancer Therapy
Systems Biology Ireland are pleased to welcome Assistant Professor Poulikos I. Poulikakos (Icahn School of Medicine at Mount Sinai, New York) who will present a guest lecture entitled 'Targeting RAF for cancer therapy. Basic mechanisms and clinical implications' on Friday 2nd December 2016 from 10am in the UCD Charles Institute, Seminar Room.
Mutations in the serine/threonine kinase BRAF are found in about 8% of human tumors, including more than 50% of melanomas. RAF inhibitors prolonged survival of melanoma patients with mutant-BRAF tumors, but resistance limits their effectiveness. In addition, RAF inhibitors showed only modest clinical activity when used for cancers other than melanomas, such as in patients with colorectal and thyroid mutant-BRAF tumors.
Clinical evidence indicates that potent and durable ERK inhibition in the tumor is required for complete responses, suggesting that a major factor that limits clinical efficacy of these drugs is insufficient inhibition of RAF. The Icahn Research Group have found previously that the effectiveness of RAF inhibitors, certain adverse effects, such as second site tumors reported in a portion of patients, and mechanisms of clinical drug resistance, are all related to the unique biochemical mechanism of RAF inhibitor action. Unlike most kinase inhibitors that suppress their target in all cells, current clinical RAF inhibitors selectively suppress BRAF only in tumors expressing mutant BRAF. In normal or tumor cells expressing wild-type BRAF, these drugs paradoxically activate BRAF and downstream signaling.
Despite significant contributions, a unifying mechanistic model has been lacking. Recently, a number of next generation RAF inhibitors with diverse structural properties have entered preclinical or clinical development, but the most appropriate clinical context for their use remains elusive. By investigating a panel of structurally diverse RAF inhibitors, the Mount Sinai researchers developed an integrated model of RAF inhibitor action as the combined outcome of distinct allosteric mechanisms. Drug resistance due to dimerization is determined by the active (“in”) or inactive (“out”) position of the αC-helix of RAF kinase stabilized by inhibitor, whereas inhibitor-induced RAF priming and dimerization are the consequence of inhibitor-induced formation of the RAF/RAS-GTP complex in cells.
The model predicts the biochemical effect of any RAF inhibitor based on its structural properties and the cellular context and provides a blueprint for the development of rationally designed RAF inhibitors and RAF inhibitor-based therapies. Therapeutic strategies including next generation αC-helix-IN inhibitors are predicted to be more effective in multiple mutant BRAF-driven tumors, including colorectal and thyroid BRAFV600E cancers, in which first generation RAF inhibitors have been ineffective.
About Systems Biology Ireland
Systems Biology Ireland (SBI) designs new therapeutic approaches to cancer. Our research enables development of technologies that can be used for early identification of responsive patient groups and accelerated discovery of new combination therapies. [More]