Exploiting genetic dependencies in SMARCA4-mutant cancers

Sidong Huang, PhD
Associate Professor
Department of Biochemistry
McGill University
Rosalind and Morris Goodman Cancer Institute

This conference is hosted by Éric Lécuyer, PhD. This conference is part of the 2024-2025 IRCM conference calendar.

About this conference
SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodelling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 occurs in a subset of cancers associated with very poor patient outcome. These SMARCA4/2-deficient cancers remain difficult to treat as they rarely harbour known druggable mutations and are resistant to conventional chemotherapies. 

Using systematic functional genetics and complementary biochemical approaches, we aim to understand disease mechanisms and uncover druggable targets of SWI/SNF-deficient cancers. Through this approach, we have uncovered several genetic vulnerabilities of SMARCA4/2-loss that can be exploited therapeutically using approved cancer drugs such as CDK4/6 inhibitors. Additionally, our recent research reveals that SMARCA4/2-loss causes altered metabolic homeostasis in cancer cells, sensitizing them to inhibitors targeting oxidative phosphorylation and glutamine metabolism, as well as a dietary strategy to inhibit glutamine uptake. Furthermore, we are investigating novel treatment strategies and developing genetically engineered mouse models to explore tumorigenesis driven by SMARCA4/2 loss. These models, featuring intact immune systems, will enable us to better evaluate candidate therapeutics and assess potential synergies with immune checkpoint blockade for effectively treating SWI/SNF-deficient cancers
 

About Sidong Huang
Dr. Sidong Huang is an Associate Professor in the Department of Biochemistry and Rosalind and Morris Goodman Cancer Institute at McGill University. He is also the scientific director of the McGill Platform for Cellular Perturbation. Dr. Huang obtained his PhD in Biochemistry and Molecular Biology from the University of California, San Francisco in 2003, under the supervision of Dr. Erin O’Shea. He then joined the laboratory of Dr. Rene Bernards at the Netherlands Cancer Institute for his postdoctoral training in cancer genetics and functional genomics. In 2013, he established his independent research group at McGill University, using functional genomic tools to study cancer-relevant pathways and to guide cancer therapy. Dr. Huang’s work has uncovered novel resistance mechanisms to cancer therapeutics, identified new treatment strategies, and led to the establishment of clinical trials. One of his studies has led to an approved drug combination co-targeting BRAF and EGFR to treat metastatic BRAF mutant colorectal cancer patients. His current research focuses on SWI/SNF-deficient cancers, which has resulted in a phase 2 clinical study testing an FDA approved CDK4/6 inhibitor for treating SMARCA4-mutant cancers.

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