In TNBC c-MET increases PARP enzymatic activity and promotes resistance to PARP inhibitors.
Major finding: In TNBC c-MET increases PARP enzymatic activity and promotes resistance to PARP inhibitors.
Mechanism: c-MET binds to and phosphorylates PARP at Tyr907, blocking its interaction with PARP inhibitors.
Impact: Combined treatment with PARP and c-MET inhibitors may prevent resistance to PARP inhibition.
PARP is recruited to reactive oxygen species (ROS)–induced DNA damage sites, where it is involved in the DNA-repair process. Thus, PARP inhibitors can prevent DNA repair and promote cell death, and have shown promise as cancer therapeutics. However, many tumors exhibit resistance to PARP inhibitors. Du and colleagues investigated the mechanism of resistance in triple negative breast cancer (TNBC) cells. PARP1 activity was associated with ROS, which can activate receptor tyrosine kinases (RTK), and a screen identified three RTKs that associate with PARP in response to ROS, of which MET was the only RTK more highly expressed in TNBC than non-TNBC. Under oxidative stress, c-MET was transported to the nucleus where it interacted with PARP, and combined treatment with PARP and c-MET inhibitors increased the sensitivity of TNBC cells to PARP inhibition. TNBCs often harbor mutations in or downregulation of BRCA1/2, and reduction of BRCA1 or BRCA2 expression resulted in increased sensitivity to PARP inhibitors only in cells with low c-MET levels. The kinase activity of c-MET was required to promote the DNA-repair function of PARP via phosphorylation at tyrosine 907 (pY907), and the phosphorylation reduced binding to PARP inhibitors. Combined treatment with PARP and c-MET inhibitors potentiated the effects of PARP inhibition, in vitro and in xenograft tumor models, resulting in reduced tumor growth accompanied by increased apoptosis and DNA damage. Additionally, this combination was well tolerated in mice. Similar results were observed in a lung cancer xenograft model. Taken together, these findings indicate that phosphorylation of PARP at Y907 may be a useful biomarker for PARP inhibition in patients, and that c-MET promotes resistance to PARP inhibitors, suggesting that combined inhibition with c-MET may be effective in reducing resistance to PARP inhibitors.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
- ©2016 American Association for Cancer Research.