The Genetic Drivers and Therapeutic Vulnerabilities of Metastatic Breast Cancer

Abstract The understanding of genetic basis and potential therapeutic targets for metastatic breast cancer (mBC) remains limited. Here we systematically identify the genetic and epigenetic causes underlying breast cancer metastasis from clinically defined alterations through multiplexed CRISPR knockout and base editing screens in various models. Multiple drivers converge on the down-regulation of SMARCA1, a core component of ISWI chromatin-remodeling complexes, to drive metastasis, largely through potentiating TGFβ signaling. Using druggable gene CRISPR screens, we identify SOD1, a key antioxidant enzyme, as a prominent vulnerability in mBC. We further validate the in vivo efficacy of SOD1 pharmacological inhibitor LCS-1 in treating mBC in multiple preclinical models. The exacerbated SOD1 vulnerability in mBC is due to elevated TGFβ signaling which impinges on mitochondrial homeostasis, thereby resulting in superoxide radical overload and subsequently triggering ferroptosis. Together, our work provides a comprehensive landscape on the genetic basis and informs therapeutic interventions for mBC.