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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA132383-07
Application #
8741941
Study Section
Special Emphasis Panel (ZCA1-SRLB-Y)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
7
Fiscal Year
2014
Total Cost
$54,392
Indirect Cost
$16,062
Name
New Mexico State University Las Cruces
Department
Type
DUNS #
173851965
City
Las Cruces
State
NM
Country
United States
Zip Code
88003
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