Characterizing the Role of the SWI/SNF Chromatin Remodeling Complex in the Development of Melanoma

Abstract

The SWI/SNF complex is a multiunit chromatin remodeling complex required for normal cell development. Mutations within SWI/SNF are associated with rapid tumor formation and aggressive progression of melanoma and other cancers. SWI/SNF dysregulation can alter gene expression globally across multiple oncogenic pathways. By bypassing signaling molecules targeted by current drugs, aberrant SWI/SNF complexes create unique challenges for cancer therapy.

Given these challenges, we aim to define the molecular alterations in melanoma upon loss of SWI/SNF and determine whether its dysregulation produces characteristic dependencies on alternative epigenetic pathways. Identification of these synthetically lethal vulnerabilities may uncover novel epigenetic mechanisms in oncogenesis.

We generated stable melanoma cell lines with precise knockdown efficiencies of SWI/SNF subunits using short hairpin RNAs and single cell cloning. Using this pool of SWI/SNF mutant cells, we assayed 100 compounds targeting epigenetic regulators. We identified multiple independent dependencies in SWI/SNF-deficient tumor cells vulnerable to synthetic inhibition. These targets also provide opportunities for synergistic combination with other treatment modalities. In addition, we show crosstalk between the SWI/SNF complex and MITF pathway that alters cancer cell phenotype. These findings offer insight into the poorly understood mechanisms by which SWI/SNF dysregulation contributes to melanomagenesis and uncover targetable vulnerabilities in these tumors.