The Promise of Combining Inhibition of PI3K （结合抑制PI3K的承诺）.pdf

VIEWS IN THE SPOTLIGHT The Promise of Combining Inhibition of PI3K and PARP as Cancer Therapy Farah L. Rehman, Christopher J. Lord, and Alan Ashworth Summary: Analyses of in vitro and patient-derived in vivo models of breast cancer reveal that a combination of inhibitors of the enzymes PARP and phosphoinositide 3-kinase (PI3K) is a potentially effective treatment regimen for breast cancer tumors with elevated activity of the PI3K pathway. Cancer Discov; 2(11); 982–4. ©2012 AACR. Commentary on Ibrahim et al., p. 1036 (9). Commentary on Juvekar et al., p. 1048 (10). PARP inhibitors are a class of developmental anticancer Second, based on preclinical studies showing additive agents that exert their cytotoxic effect by modulating the repair or synergistic effects of combining PARP inhibitors with a of DNA damage ( 1 ). Although originally developed as chemo- number of chemotherapeutic agents, clinical trials assessing sensitizers, PARP inhibitors are also able to elicit synthetic PARP inhibitor drug combination regimens have been con- lethality in tumor cells carrying loss-of-function mutations in ducted. However, combinations with temozolomide, plati- tumor suppressor genes such as BRCA1 and BRCA2 ( 1 ). Loss of num salts, paclitaxel, or gemcitabine have generally shown these genes causes a defi ciency in the homologous recombina- exacerbation of toxicity, most often myelosuppression, tion (HR) DNA double-strand break (DSB) repair pathway; it is requiring dose reductions ( 1 ). This suggests that, although thought that the loss of HR restricts the ability of cells to repair there may be an additive or even syne