DNA methyltransferase inhibitors induce a BRCAness phenotype that sensitizes NSCLC to PARP inhibitor and ionizing radiation

Abstract

A minority of cancers have breast cancer gene (BRCA) mutations that confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), but the role for PARPis in BRCA-proficient cancers is not well established. This suggests the need for novel combination therapies to expand the use of these drugs. Recent reports that low doses of DNA methyltransferase inhibitors (DNMTis) plus PARPis enhance PARPi efficacy in BRCA-proficient AML subtypes, breast, and ovarian cancer open up the possibility that this strategy may apply to other sporadic cancers. We identify a key mechanistic aspect of this combination therapy in nonsmall cell lung cancer (NSCLC): that the DNMTi component creates a BRCAness phenotype through downregulating expression of key homologous recombination and nonhomologous end-joining (NHEJ) genes. Importantly, from a translational perspective, the above changes in DNA repair processes allow our combinatorial PARPi and DNMTi therapy to robustly sensitize NSCLC cells to ionizing radiation in vitro and in vivo. Our combinatorial approach introduces a biomarker strategy and a potential therapy paradigm for treating BRCA-proficient cancers like NSCLC.

Epigenetic targeting of DNA repair in lung cancer

“…We and others have reported that PARPi increases DSB formation and confers radiosensitization in lung cancer models through a PARP-trapping mechanism (15,16). The work reported here suggests that DNMTi can augment PARPi radiosensitization and is a combination strategy with significant translational potential (6). The observation that AZA also down-regulates factors contributing to NHEJ, a nontemplate-dependent DSB repair pathway associated with imprecise repair, may further contribute to this effect.…”

“…In the current report, the Rassool laboratory provides mechanistic insights into this combination effect, using ionizing radiation to initiate DNA damage in lung cancer models (6). The investigators find that DNMT inhibition abrogates both HR and nonhomologous end joining (NHEJ), 2 key complementary DSB repair pathways, in NSCLC cells.…”

“…Both HR and NHEJ are important for radiotherapy-induced DNA DSB repair, with most radiotherapy-generated DSBs being repaired by NHEJ. The authors show AZA down-regulates Ku80, an important component of the Ku heterodimeric complex necessary for NHEJ (6).…”

“…Even expanding beyond BRCA to >100 HR core and related genes, only about 5% of human tumors (and a similar fraction of NSCLC) harbor biallelic alterations in a known HR target gene (10). Potentially addressing the supermajority of NSCLC that is HR proficient, Abbotts et al (6) demonstrate a promising strategy whereby epigenetic targeting using DNMTi can pharmacologically induce a BRCA-like HR deficiency state in NSCLC, sensitizing these cells to PARPi. This strategy complements a broader array of recent efforts to expand the population that may benefit from induced HR deficiency, as reviewed in ref.…”

Inhibition of Xanthine Oxidoreductase Enhances the Potential of Tyrosine Kinase Inhibitors against Chronic Myeloid Leukemia

“…Drug interaction was analyzed by the median-effect method as described by Chou-Talalay [24], as it has been extensively endorsed in the scientific literature [25][26][27][28][29]. The combination index (CI), calculated with the CalcuSyn software (Biosoft, Cambridge, UK), establishes the interaction between drugs: Synergy (CI < 1), additivity (CI = 1), or antagonism (CI > 1).…”