DNA methyltransferase inhibitors induce a BRCAness phenotype that sensitizes NSCLC to PARP inhibitor and ionizing radiation
Menée in vitro et à l'aide d'un modèle murin de cancer du poumon non à petites cellules, cette étude démontre que les inhibiteurs de l'ADN méthyltransférase, en favorisant la survenue de caractérisques tumorales présentes dans les tumeurs associées à une mutation d'un gène BRCA, sensibilisent les cellules cancéreuses aux inhibiteurs de PARP et aux rayonnements ionisants
We introduce a key role for low doses of DNA methyltransferase inhibitors (DNMTis) in reprogramming the DNA repair transcriptome and creating a homologous recombination defect (HRD), sensitizing to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) in breast cancer gene (BRCA)-proficient nonsmall cell lung cancer (NSCLC), which are not clinically responsive to PARPis. The nonhomologous end-joining pathway is also downregulated by DNMTis, generating sensitivity to radiation therapy (RT). The significant increases in antitumor effects with DNMTi and PARPis in combination with RT suggest a potentially potent therapeutic strategy for patients with BRCA-proficient NSCLC, for whom limited therapy is available.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.