Combination of Volasertib and Rapamycin Inhibits the Regrowth of TSC2-Deficient Tumors

ABSTRACT Mutations in TSC1 and TSC2 lead to hyperactivation of mTORC1 and cause Tuberous Sclerosis Complex (TSC) and pulmonary Lymphangioleiomyomatosis (LAM). Rapamycin and rapalogs are potent inhibitors of mTORC1 activity and are approved for the treatment of TSC and LAM. Nevertheless, rapalogs do not cause tumor cell death, and cessation of therapy leads to tumor regrowth. Polo-like kinase 1 (PLK1) interacts with and phosphorylates TSC1, and PLK1 inhibition induces apoptosis and attenuates autophagy in TSC1/TSC2-deficient cells. Here we report that the PLK1 inhibitor volasertib decreases the viability and survival and induces apoptosis in 621-101 cells, a TSC-deficient renal angiomyolipoma cell line from a LAM patient. Combined with rapamycin, volasertib further decreased the survival of 621-101 cells. In vivo , volasertib reduced short-term mouse lung colonization by TSC2-deficient cells and decreased the growth of TSC2-deficient subcutaneous tumors. Mice treated with a combination of volasertib and rapamycin had slower tumor relapse after discontinuation of treatment, compared to rapamycin only. Approximately 35 days after discontinuation of treatment, we observed persistent apoptotic markers and gene expression changes for type I interferon signaling in the regrowth tumors from combination-treated mice, compared to rapamycin only. Notably, combination treatment potently inhibited the growth of subcutaneous tumors derived from the rapamycin-refractory cell line ELT3-245. Taken together, our current work demonstrates that for the management of TSC and LAM disease combination of mTORC1 and PLK1 inhibitors in some cases may be advantageous over currently used rapalog monotherapies.