Potentiation Of The Anti-Proliferative And Cytotoxic Activity Of Arq 197 & Gemcitabine With A Pulsatile Exposure Regimen

ARQ 197 is a small molecule that inhibits c-MET kinase and is being evaluated clinically both as a monotherapy and in combination with other anti-cancer agents, including gemcitabine. Prompted by clinical observations, in vitro studies were conducted to explore the combination of ARQ 197 and gemcitabine with the goal of determining the most effective exposure regimen and to further refine the strategy of an ongoing phase 1b combination clinical trial. Gemcitabine and ARQ 197 both induce cell cycle arrest in cancer cells, but in different phases. Gemcitabine induces a G1/S-phase arrest, while ARQ 197 arrests cells in the G2/M phase. We hypothesized that the efficacy of combining these two agents might be enhanced by deliberate pulsatile treatment with ample time allowed for gemcitabine-treated cells to re-enter the cell cycle and to therefore potentially increase their vulnerability to ARQ 197-induced cell cycle arrest and apoptosis. A 7-day MTS cytotoxicity assay was employed in which the cells were seeded on Day 0, treated with gemcitabine for 24 h on Day 2, drug free medium added on Day 3, and ARQ 197 added on Day 5 for 24 h and then replaced with drug free medium. Cell viability was assayed with MTS reagent at the end of Day 7. To determine whether this pulsatile schedule was more advantageous then a regimen with no intervening “drug holiday”, control cultures were not replenished with drug free medium on Day 3 and ARQ 197 was added on Day 5. When the pulsatile schedule was employed, the combinatorial cytotoxicity of these two agents was significantly enhanced in several cancer cell lines (including NSCLC, bladder, pancreatic, breast, ovarian and uterine carcinomas). Mechanistic studies confirmed the G1/S-phase arrest of gemcitabine-treated cells, and G2/M arrest was observed following exposure to ARQ 197 in this regimen. Furthermore, this potentiation was also observed if ARQ 197 was exposed to the cancer cells as the first agent on Day 2 and gemcitabine added as the second agent on Day 5, as long as the pulsatile regimen was employed. These data suggest that modifications to dosing schedules of ARQ 197 and gemcitabine may improve the potential for synergistic anti-tumor activity in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5376. doi:10.1158/1538-7445.AM2011-5376