DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer

Abstract

Non-small cell lung cancers (NSCLC) are commonly treated with a platinum-based chemotherapy such as cisplatin (CDDP) in combination with ionizing radiation (IR). Although clinical trials have demonstrated that the combination of CDDP and IR appear to be synergistic in terms of therapeutic efficacy, the mechanism of synergism remains largely uncharacterized. We investigated the role of the DNA damage response (DDR) in CDDP radiosensitization using two NSCLC cell lines. Using clonogenic survival assays, we determined that the cooperative cytotoxicity of CDDP and IR treatment is sequence dependent, requiring administration of CDDP prior to IR (CDDP-IR). We identified and interrogated the unique time and agent-dependent activation of the DDR in NSCLC cells treated with cisplatin-IR combination therapy. Compared to treatment with CDDP or IR alone, CDDP-IR combination treatment led to persistence of γH2Ax foci, a marker of DNA double-strand breaks (DSB), for up to 24 hours after treatment. Interestingly, pharmacologic inhibition of DDR sensor kinases revealed the persistence of γ-H2Ax foci in CDDP-IR treated cells is independent of kinase activation. Taken together, our data suggest that delayed repair of DSBs in NSCLC cells treated with CDDP-IR contributes to CDDP radiosensitization and that alterations of the DDR pathways by inhibition of specific DDR kinases can augment CDDP-IR cytotoxicity by a complementary mechanism.

Loss of tumour-specific ATM protein expression is an independent prognostic factor in early resected NSCLC

“…This is consistent with recent reports and our own data (not shown) that have shown increased platin-induced cytotoxicity in vitro in ATM- and DDR-deficient cell lines [32, 33]. Additionally, ATM-loss in breast cancer If this is the case, our data suggests that while patients with early stage ATM-proficient NSCLC receive little-to-no advantage from adjuvant therapy, those with ATM-deficient tumours could benefit greatly under current standard treatment regimens, or even low dose therapy.…”

DNA end-resection in highly accessible chromatin produces a toxic break

“…Classically, the inhibition of DNA repair pathways has been associated with decreased cell survival 45,49 . Indeed, the inhibition of Mre11 or DNA-PKcs can perturb colony outgrowth in -irradiated cells (Suppl.…”

Coroglaucigenin enhances the radiosensitivity of human lung cancer cells through Nrf2/ROS pathway

“…Ionizing radiation (IR) causes DNA nucleotide modifications, single and double strand DNA breaks (SSBs and DSBs), both directly and indirectly via formation of free radicals and ROS. It is generally estimated that approximately two-thirds of IR-induced DNA damage is caused by the latter [11, 12]. Cells have therefore developed efficient systems for maintaining their genomic integrity, such as the DNA damage response (DDR).…”