Ariel Leyte-Vidal
Understanding and Overriding Resistance to Asciminib in Chronic Myeloid Leukemia
Summary
Chronic myeloid leukemia (CML) is a blood cancer that arises from the fusion of two genes, BCR and ABL1. The resulting BCR-ABL1 protein promotes uncontrolled growth of blood cells. CML can be treated with drugs that block the activity of BCR-ABL1, but resistance occurs in some patients. At the molecular level, resistance to these drugs is most commonly due to mutations that prevent their ability to bind BCR-ABL1. In 2021, the FDA approved a drug called asciminib, which binds to a different site on the BCR-ABL1 protein than previous drugs, locking the protein in an inactive state and stopping it from causing uncontrolled cell growth. However, some of the first cases of asciminib resistance are now emerging, and to date, all are associated with new mutations in BCR-ABL1. I hypothesize that most of these mutations will not impact drug binding but rather prevent the changes that asciminib normally causes to inactivate BCR-ABL1. Using assessments of drug binding and protein structures, my work seeks to molecularly dissect the mechanisms responsible for resistance to asciminib.
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.
