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.
One of the major challenges to the cell is to ensure genome stability, which can be compromised through endogenous errors or exogenous DNA damaging agents, such as ionizing radiation or common chemotherapeutic agents. To maintain genome stability the cell has a multifaceted line of defense, including cell cycle checkpoints and DNA damage repair pathways. RAD54B is involved in many of these pathways and thus exhibits a role in maintaining and repairing genome stability following DNA damage. RAD54B is involved in cell cycle regulation after DNA damage and participates in homologous recombinational repair, which ensures the precise repair of the most deleterious DNA lesions, double-stranded breaks. This review focuses on structural aspects of RAD54B, molecular functions associated with its cellular roles in preventing genome instability, and how aberrant function contributes to oncogenesis. By understanding how aberrant RAD54B expression and/or function can contribute to oncogenesis, novel therapeutic approaches that specifically exploit these aberrant genetics are now being explored for precision medicine targeting. RAD54B represents an ideal candidate for synthetic genetic therapeutic approaches (synthetic dosage lethality or synthetic lethality), which are designed to target the specific genetics associated with cancer formation. These therapeutic approaches represent a precision-based approach, which is ideal as we are now entering the era of precision medicine.
Objectives: Advanced pancreatic cancer (APC) disproportionately impacts older adults. Randomized trials demonstrate improved overall survival (OS) with combination chemotherapy including 5-fluorouracil, irinotecan, leucovorin, and oxaliplatin (FOLFIRINOX) or nab-paclitaxel and gemcitabine compared with gemcitabine alone, but with increased toxicity. Older adults are at increased risk of side effects from chemotherapy. The aim of this study was to assess the efficacy and toxicity of chemotherapy in older adults with APC. Methods: Patients diagnosed with APC from 2011 to 2016 were identified using the Manitoba Cancer Registry. Patient and treatment characteristics, toxicity, and outcomes of patients 65 years of age and above treated with palliative chemotherapy were compared by treatment regimen. OS was assessed using the Kaplan-Meier method. A Cox regression was used to identify independent predictors of OS. Results: A total of 87 patients aged 65 years and above received palliative chemotherapy: 52 (59.7%) FOLFIRINOX, 21 (24.1%) nab-paclitaxel and gemcitabine, and 14 (16.1%) gemcitabine, with a median age of 69 (65 to 84), 75 (65 to 88), and 73 (67 to 82), Eastern Cooperative Oncology Group (ECOG) performance status difference in hematologic toxicity between regimens (P=0.807). An increase in nonhematologic toxicity was seen with FOLFIRINOX (P<0.001), specifically neuropathy (P=0.008), fatigue (P<0.001), and nausea/vomiting (P=0.008). FOLFIRINOX was associated with improved radiologic response (P=0.05) and OS (P=0.035). PS, baseline carbohydrate antigen 19-9 level, and chemotherapy regimen were independent predictors of survival. Conclusions: FOLFIRINOX is associated with improved response and OS in older adults with APC. FOLFIRINOX has a manageable safety profile in this population and should be considered in fit older adults with APC.
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