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

Abstract

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.

Association between PTCH1 and RAD54B single‐nucleotide polymorphisms and non‐syndromic orofacial clefts in a northern Chinese population

“…23. 24 We have confirmed that RAD54B was associated with a decreased risk of NSOC in the present study. In the same period, RAD54B also showed abnormal expression in many cancer types, including colorectal cancer.…”

“…Its expression or function are pathogenic factors in the development and progression of cancer. 24 Subsequently, Chang et al 25 have confirmed that RAD54B could affect the prognosis of lung adenocarcinoma patients. These results revealed that RAD54B can not only lead to congenital malformations such as NSOC, but also play a role in the development of cancer by affecting genomic stability.…”

“…In the same period, RAD54B also showed abnormal expression in many cancer types, including colorectal cancer. Its expression or function are pathogenic factors in the development and progression of cancer . Subsequently, Chang et al have confirmed that RAD54B could affect the prognosis of lung adenocarcinoma patients.…”

The enigmatic oncogene and tumor suppressor‐like properties of RAD54B: Insights into genome instability and cancer

“…RAD54B represents an excellent candidate to exploit using a SL approach as it is somatically mutated or deleted in numerous cancer types (Figure A), and it encodes a protein with tumor suppressor‐like properties. Indeed, a number of genetic studies have already identified unique SL interactors for RAD54B including; (1) flap endonuclease‐1 ( FEN1 ), (2) superoxide dismutase 1 ( SOD1 ), (3) DNA Ligase IV ( LIG4 ), and (4) PARP1 …”

“…Oh et al identified the SL interaction between RAD54B and LIG4 because the dual knockout of these genes resulted in no viable clones. Finally, McAndrew et al showed that RAD54B is SL with PARP1 and further showed that simultaneous inhibition of both PARP1 and SOD1 synergized and enhanced killing within a population of RAD54B ‐deficient cells …”