Ariel Leyte-Vidal
Disruption of Allostery as a Novel Mechanism of TKI Resistance in CML
Abstract
Asciminib is a first-in-class allosteric inhibitor of BCR::ABL1, a fusion gene that drives chronic myeloid leukemia (CML) and has shown promising efficacy in patients. However, resistance to asciminib has been observed, highlighting the need to understand the mechanisms underlying resistance. This proposal focuses on elucidating the molecular mechanisms by which clinically relevant point mutations in BCR::ABL1 can cause resistance to asciminib. Our central hypothesis is that these mutations, located at a significant distance from the drugs binding site, may confer resistance by a novel mechanism that disrupts the allosteric effect of asciminib, despite retaining the ability to bind to the drug. We propose to investigate this hypothesis through in vitro analyses and structural biology techniques. This research aims to advance our understanding of kinase regulation, identify clinically relevant vulnerabilities, and ultimately guide the development of more effective therapeutic strategies
I am profoundly honored to receive the PhRMA Foundation fellowship, which acknowledges my efforts in hematology research and strengthens my commitment to advancing patient care. With the support of this grant, I aim to uncover a novel mechanism of resistance to kinase inhibitor treatment for chronic myeloid leukemia (CML), which will advance the understanding of kinase cancer biology and establish a model for elucidating mechanisms of resistance to an emerging class of allosteric molecular targeted cancer therapies. Importantly, my findings will help patients avoid ineffective and unnecessary delay in access to treatment.
