A-Lien Lu-Chang
University of Maryland, USA
Title: SIRT1 and Chk1 inhibition as novel therapeutic strategies in melanoma
Biography
Biography: A-Lien Lu-Chang
Abstract
Melanoma is the deadliest form of skin cancer. Mutational activation of the protein kinase BRAF accompanied by loss of the tumor suppressor PTEN is the most common cause of melanomagenesis. Targeted therapy against BRAF mutation represents one of the most significant advances in the treatment of melanoma. However, response to BRAF inhibitor (BRAFi) PLX4032 (vemurafenib) is not durable because many patients acquire drug resistance. Thus, therapies that can overcome resistance to the drug are urgently needed. We have demonstrated that a specific inhibitor of protein deacetylase SIRT1 (SIRT1i) and BRAFi synergistically reduces the viability of melanoma cells and SIRT1i slows melanoma tumor growth in mouse xenografts. Cell cycle checkpoints are very promising targets for anticancer therapies because they control cancer cell responses to chemotherapy and radiation. Currently, Chk1 inhibitors (Chk1i) are being tested clinically for several cancers. Our novel findings show that a specific Chk1i significantly decrease cell proliferation, but even more impressively, triggers PLX4032-resistant melanoma cells regaining the sensitivity to the drug. We hypothesize that SIRT1i and Chk1i will augment the potency of BRAFi against melanoma. The use of combinatorial therapies will improve the outcomes and curtail the resistance to BRAFi in melanoma. Our work holds promise for finding novel targets for anti-cancer therapies and will provide new therapy options for melanoma patients.