Novel Orally Bioavailable ATM Inhibitor Radiosensitizes Glioma
Karlin and Allen et al. Page 1637
Surgery and chemoradiation are the standard of care for glioblastoma multiforme (GBM), a devastating and incurable cancer with few clinical options. Small molecule inhibitors targeting ATM, a master regulator of the DNA damage response, are currently in clinical development. Karlin, Allen, and colleagues report an experimental, blood-brain barrier penetrating ATM kinase inhibitor that prolongs the survival of mice with orthotopic tumors in combination with radiation. The enhanced response seen with tumors having dysfunctional p53 signaling is attributed to increased mitotic catastrophe. These results define a mechanism for preferential responses in p53-defective cancers and may lead to improved, selective treatment of GBM.
TAS6417 as a Novel EGFR-TKI Specific to Exon 20 Insertions
Hasako et al. Page 1648
Development of EGFR-tyrosine kinase inhibitor (TKI) with selectivity against exon 20 insertion mutations over wild-type is a major challenge for the treatment of non-small-cell lung cancer (NSCLC) driven by EGFR harboring such mutations. Hasako and colleagues identified TAS6417 which is a novel small molecule EGFR-TKI and exhibits selective inhibition of exon 20 insertion mutations over wild-type in vitro and in vivo, achieving remarkable antitumor efficacy in preclinical model including NSCLC patient-derived xenograft model. These findings support clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.
EYA3 and Tumor Angiogenesis
Wang et al. Page 1659
EYA3 is a protein tyrosine phosphatase that promotes survival of cells after DNA damage. In this study, Wang and colleagues show that host vascular endothelial cell EYA3 promotes tumor angiogenesis, and that tumor cell EYA3 promotes survival and proliferation of tumor cells. Pharmacological inhibition of the EYA3 protein tyrosine phosphatase activity attenuates tumor growth and tumor angiogenesis by targeting both host and tumor cells. Simultaneously targeting the tumor vasculature and tumor cells is an attractive therapeutic strategy since it could counter the development of the more aggressive phenotype known to emerge from conventional anti-angiogenic agents.
AZD6738 Synergizes with Gemcitabine to Inhibit PDAC
Wallez et al. Page 1670
Rising incidence and extreme mortality rate of PDAC, engender a major unmet clinical need that urgently requires novel therapeutic strategies. Small molecule inhibitors targeting DNA damage response pathways hold promise, but rational combinations with conventional therapies require investigations. Here, Wallez and colleagues report that the ATR inhibitor, AZD6738, and gemcitabine potently synergize to inhibit proliferation of PDAC cell lines, and demonstrate that this combination is well tolerated, inducing tumor regression in preclinical cancer models. Together, these data support clinical testing of this innovative combination in patients with PDAC, and more generally in solid tumors with high levels of replication stress.