Doxorubicin is one of the most effective and widely used chemotherapy agents for breast cancer. However, resistance to this anthracycline agent is common, leading to treatment failure and poor prognosis. Triple negative breast cancer (TNBC), a clinical subtype type seen disproportionately in African American and Latina women (1, 2), is characterized by higher recurrence and lower overall survival following anthracycline treatment (1, 3). Developing targeted therapies for TNBC, especially those that do not respond to doxorubicin, is the most urgent priority for the clinical treatment of this aggressive disease (4). Several mechanisms have been implicated in doxorubicin resistance, including an increase in drug efflux pathways (5), epidermal growth factor receptor signaling (6), and mutations in the tumor suppressors ATM or p53 (7-9), but these findings have not been widely translated for clinical benefit. Recent studies from whole genome sequencing of over 1,000 breast cancers reveal that the tumor suppressor p53 is mutated in 43-62% (10, 11), making it one the most commonly mutated genes in this cancer type. p53 is required for DNA damage induced apoptosis, so therapies designed to increase the sensitivity of p53 mutant breast cancer cells to genotoxic therapy would be immensely beneficial. We recently reported that the DNA repair protein DNAPK regulates p53 independent apoptosis (12), pointing to a novel pathway to sensitize p53 mutant tumors. To identity additional genes that regulate p53 independent cell death, we performed a kinome wide siRNA doxorubicin sensitizer screen with p53 mutant cancer cells. The doxorubicin survival genes identified function in G2yM cell cycle regulation, DNA repair, and apoptosis. Based on these findings, we hypothesize that targeting these doxorubicin survival genes will lead to p53 independent apoptotic or mitotic celt death and will sensitize breast tumors to doxorubicin. Our partnership combines expertise in DNA repair, cancer biology, and functional genetics together with the outstanding research environments of the FHCRC and NMSU.
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