The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancerin vivo

Abstract

ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts.

ATM Mutations in Cancer: Therapeutic Implications

“…Notably, ATM-deficient lung cancer xenografts were particularly sensitive to a combination of cisplatin and (78). In studies with primary leukemic cells from patients with chronic lymphocytic leukemia, AZD6738 had superior cytotoxicity in CLL cells induced to divide (79), and in ATM-or TP53-mutated CLL cells (80).…”

ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma

“…These experiments were motivated by recent reports suggesting that ATM depletion or loss might be associated with ATR inhibitor sensitivity in chronic lymphocytic leukemia (42). In addition, the ATR inhibitor AZD6738 was recently shown to potently synergize with cisplatin in ATM-deficient non-small cell lung cancer cells (43). Furthermore, combined cisplatin and AZD6738 treatment was shown to induce robust shrinkage of xenograft tumors derived from KRAS-mutant and ATM-defective human H23 lung adenocarcinoma cells (43).…”

“…In addition, the ATR inhibitor AZD6738 was recently shown to potently synergize with cisplatin in ATM-deficient non-small cell lung cancer cells (43). Furthermore, combined cisplatin and AZD6738 treatment was shown to induce robust shrinkage of xenograft tumors derived from KRAS-mutant and ATM-defective human H23 lung adenocarcinoma cells (43). To further interrogate the effects of Thus, in summary, our data indicate that homozygous Atm deletion in KP murine lung adenocarcinoma cell lines is associated with two distinct molecular vulnerabilities, namely an actionable dependence on PARP1 (Fig.…”

53BP1 inhibits the migration and regulates the chemotherapy resistance of ovarian cancer cells

“…Cisplatin is commonly used by gynecologists to kill tumor cells by inducing DNA damage, promoting cell cycle arrest and increasing the rate of apoptosis (6,7). Previous studies have reported the following mechanisms underlying chemotherapy resistance: Certain tumor cells exhibit enhanced DNA repair functions and a weakened apoptotic process, with the transformation to epithelial stroma facilitating the secretion of matrix protein enzymes, including matrix metalloproteinase (MMP)-2 and MMP-9, which enable these tumor cells to break through the basement membrane, metastasize and invade.…”