Phosphorylation-dependent targeting and activity of cBAF chromatin remodeling complexes promotes oncogenic kinase signaling in cancer

Claudia Gentile, PhD
Postdoctoral Research Fellow
Department of Pediatric Oncology
Dana-Farber Cancer Institute
Harvard Medical School
Howard Hughes Medical Institute (HHMI)
Boston, MA, USA
 

This conference is hosted by Marie Kmita, PhD. This conference is part of the the IRCM Early-Career Scientist Seminar Series (ECS3), a groundbreaking initiative whose mission is to showcase early career scientists. This is a great opportunity to discover the exciting projects of these researchers in training in front of a multidisciplinary audience.

About this conference
Aberrant kinase activation represents a frequent determinant of human cancer and has inspired the development of a widely used class of small molecule inhibitors. However, the impact of hyperactive signaling cascades on the structure and function of key gene regulatory machineries remains elusive. Here, we find that mSWI/SNF chromatin remodeler complex targeting and activity support the gene expression and accessibility profiles of EGFR and BRAF mutant NSCLC and melanoma, respectively, with small molecule mSWI/SNF ATPase inhibition leading to attenuated kinase pathway signaling. Notably, pharmacologic inhibition of kinases results in rapid changes in cBAF subunit phosphorylation events, which alone and in combination support key TF interactions, oncogenic gene expression, and proliferation. Together, these findings suggest mechanisms by which activities of mutant kinases lead to physical alteration of chromatin remodelers to impact the chromatin landscape permissive of kinase signaling in cancer.

About Claudia Gentile
Dr. Claudia Gentile was born and raised in Montreal, where she attended Concordia University for her Bachelor's Degree in Science. She obtained her Ph.D. in Experimental Medicine from McGill University, under the supervision of Dr. Marie Kmita at the IRCM. She is currently completing a postdoctoral fellowship in the laboratory of Dr. Cigall Kadoch, in the department of Pediatric Oncology at Dana-Farber Cancer Institute (DFCI) and Harvard Medical School. Her postdoctoral work focuses on defining the connectivity between cell signaling pathways and epigenetic gene regulation to inform novel therapeutic opportunities in human cancer.