Editors' ChoiceCancer

FGFR inhibitors get to nuclear PTEN

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Sci. Signal.  16 Apr 2019:
Vol. 12, Issue 577, eaax6492
DOI: 10.1126/scisignal.aax6492

FGFR inhibitors block DNA repair coordinated by PTEN, enhancing radiotherapy in glioblastoma.

The phosphatase PTEN suppresses the activity of a major cell proliferation pathway in the cytoplasm; as such, its absence or functional deficiency is associated with tumor growth. However, PTEN is also found in the nucleus, where it promotes DNA repair and chromosome stability in a manner that is independent of its catalytic phosphatase activity. Depletion of PTEN increases the cytotoxic efficacy of ionizing radiation (IR) in tumor cells; however, such gene- or mRNA-targeted therapies are not yet clinically available. Ma et al. found an alternative pharmacological approach to block the DNA repair–specific function of PTEN: pharmacologically inhibiting the cell surface receptor tyrosine kinase FGFR2. IR exposure promoted the nuclear translocation—but curiously not phosphorylation—of FGFR2. This coincided with the phosphorylation of PTEN on Tyr240 (possibly directly by FGFR2), which induced a conformational change that enabled its binding first to Ki-67 and then to chromatin. Chromatin-bound PTEN/Ki-67 complexes then recruited the critical DNA repair factor Rad51. This facilitated IR-induced DNA damage repair and, consequently, survival in glioblastoma (GBM) cells. Blocking FGFR2 with the FGFR inhibitor AZD4547, a drug that is in clinical trials for lung cancer and which penetrates the blood-brain barrier, prevented the phosphorylation of PTEN on this site and its consequent chromatin interaction and DNA repair function. AZD4547 enhanced the efficacy of subsequent IR, DNA damage–inducing chemotherapies, or EGFR inhibitors (which can also cause DNA damage) and prolonged the survival of orthotopic tumor-bearing mice without any obvious organ-specific or whole-body toxicity, suggesting that this approach may increase the efficacy of various DNA damage–associated therapies in patients.

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