Research Papers:

The synthetic lethal killing of RAD54B-deficient colorectal cancer cells by PARP1 inhibition is enhanced with SOD1 inhibition

Erin N. McAndrew _, Chloe C. Lepage and Kirk J. McManus

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:87417-87430. https://doi.org/10.18632/oncotarget.13654

Metrics: PDF 1291 views  |   HTML 2457 views  |   ?  


Erin N. McAndrew1,2, Chloe C. Lepage1,2, Kirk J. McManus1,2

1University of Manitoba, Department of Biochemistry & Medical Genetics, Winnipeg, Manitoba, Canada

2Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada

Correspondence to:

Kirk J. McManus, email: [email protected]

Keywords: cancer, RAD54B, PARP1, synthetic lethality, precision medicine

Received: October 12, 2016     Accepted: November 07, 2016     Published: November 26, 2016


Colorectal cancer (CRC) is a leading cause of cancer-related death throughout the world. Despite improved screening efforts, most CRCs are diagnosed at late stages when surgery alone is not curative. Moreover, the low 5-year survival rate (~8-13%) for those living with stage IV CRC highlights the need for better treatment options. Many current chemotherapeutic approaches are non-specific and associated with side effects due to their tendency to target both normal and cancer cells. To address this issue, synthetic lethal (SL) approaches are now being explored in cancer and are defined as the lethal combination of two independently viable mutations/deletions. From a therapeutic perspective, SL interactors of genes mutated in cancer serve as candidate drug targets. The present study focuses on RAD54B, a gene that is aberrantly expressed in many cancer types, including CRC. We show that PARP1 silencing or inhibition (BMN673 or Olaparib) leads to selective killing within RAD54B-deficient cells relative to controls, and is accompanied by increases in γ-H2AX (a surrogate marker of DNA double strand breaks) and cleaved Caspase-3 (an apoptotic indicator). We further show that BMN673 synergizes with LCS-1 (an inhibitor of an established RAD54B SL interactor) to induce enhanced killing in RAD54B-deficient cells. Collectively, these data identify RAD54B and PARP1 as SL interactors, and thus reveal PARP1 as a novel candidate drug target in RAD54B-deficient CRCs. These findings further show that combinatorial chemotherapies involving multiple SL targets may promote synergistic killing within cancer cells, a strategy that may hold potential in many cancer contexts.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 13654