WEE1 Inhibition Sensitizes Pancreatic Cancer to PARP Inhibitor Radiosensitization

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In a study reported in Clinical Cancer Research, Karnak and colleagues found that WEE1 kinase inhibition increased the sensitivity of pancreas cancer to the radiosensitizing effects of poly(ADP-ribose) polymerase (PARP) inhibition.

Treatment of human pancreatic cancer AsPC-1 and MiaPaCa-2 cells with either the WEE1 inhibitor AZD1775 or the PARP inhibitor olaparib resulted in modest radiosensitization, with the combination significantly increasing radiosensitization. Use of the combination was associated with G2 checkpoint abrogation and persistent DNA damage, and WEE1 inhibition was found to reduce homologous recombination repair and prevent radiation-induced Rad51 focus formation.

In MiaPaCa-2 xenografts, olaparib produced no radiosensitization, and AZD1775 had a moderate effect (P < .05). However, the combination produced highly significant radiosensitization (P < .0001) that translated into a 13-day delay in tumor-volume doubling vs radiation alone and complete eradication of 20% of tumors.

The authors concluded: “Taken together, these results demonstrate the efficacy of combined inhibition of WEE1 and PARP inhibitors for radiosensitizing pancreatic cancers and support the model that WEE1 inhibition sensitizes cells to PARP inhibitor-mediated radiosensitization through inhibition of [homologous recombination repair] and abrogation of the G2 checkpoint, ultimately resulting in unrepaired, lethal DNA damage and radiosensitization.” ■

Karnak D, et al: Clin Cancer Res 20:5085-5096, 2014.




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