Synergistic immunostimulatory effects and therapeutic benefit of combined PARP and MEK inhibitor in RAS mutant cancer
Chaoyang Sun1,*, Jun Yin1, Yong Fang1, Yiling Lu1, Gordon B. Mills1
1Department of Systems Biology, University of Texas MD Anderson Cancer Center,
Houston, TX 77030, USA
*Corresponding Author: Chaoyang Sun
Ovarian cancer is the leading cause of death from gynecological malignancies in the United States. Approximately half of all high grade serous ovarian cancers (HGSOC) exhibit aberrations in components of the homologous recombination (HR) DNA repair pathway that likely contribute to efficacy of poly-ADP ribose polymerase (PARP) inhibitors (PARPi). However, the majority of the patients rapidly develop resistance to PARPi and relapse. Thus it is critically important to understand mechanisms of resistance to PARPi and to develop rational combination therapies to bypass the resistance.
Use a broad based unbiased proteomics study (Combinatorial Adaptive Response Therapy (CART) through Reverse phase protein array (RPPA)), we demonstrated that PARPi activated the RAS/MAPK pathway suggesting that a combination of PARPi and RAS pathway inhibitors could be effective in ovarian cancers. Strikingly, RAS mutations or RAS pathway activation rendered ovarian cancer cells, including those with BRCA1/2 mutations, resistant to PARPi. Strikingly both in vitro and in vivo the combination of PARPi with MEKi demonstrated marked synergy in RAS mutant as well as pathway activated ovarian cancers. However, many of the tumors relapsed after cessation of treatment. Thus there is a need to convert the remarkable responses to prolonged efficacy that approximates cures. Impressively, we found that the combination of PARP plus MEK inhibitors induces an immune response that participates in the response to the combination. Indeed, the efficacy of the PARPi and MEKi combination is markedly attenuated in immunodeficient mice. Mechanically, we found that BMN673 activated the innate immune pathway mediated by the stimulator of interferon genes (STING) pathway. Further, MEKi increase effector CD8+ T cells within tumors. Thus, PARPi and MEKi both impact immune responses in tumors, but through different mechanisms. Supporting this contention, the combination with PARPi, MEKi and immune checkpoint inhibitor (anti-PD-L1) remarkably increase the duration of control of KRAS mutant cancer, has the potential to cure cancers.