The majority of melanoma patients harbor mutations in the BRAF oncogene. Therefore, targeting BRAF is clinically relevant. However, response to mutant BRAF inhibitors (BRAFi) is relatively short-lived with progression free survival of only 6-7 months. Our previous report identified high expression of ribonucleotide reductase M2 (RRM2), which is rate limiting for de novo dNTP synthesis, as a poor prognostic factor in mutant BRAF melanoma patients. In this study, we investigated whether targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred both in vitro in multiple mutant BRAF cell lines and in vivo using a novel patient-derived cell line. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair gene expression and increased apoptotic markers. After discontinuing PLX4720 treatment, cells showed a marked rebound growth. However, knockdown of RRM2 attenuated this rebound growth both in vitro and in vivo, which correlated with maintenance of the senescence-associated cell cycle arrest. Implications: Inhibition of RRM2 converts the transient response of melanoma cells to BRAFi to a stable response and may be a novel combinatorial strategy to prolong therapeutic response of melanoma patients.
- Received March 19, 2016.
- Revision received May 13, 2016.
- Accepted June 6, 2016.
- Copyright ©2016, American Association for Cancer Research.