Abstract:
Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with worst prognosis. Cytotoxic chemotherapy is the mainstay of treatment for the advanced stage disease. However, response rates to these agents are limited and many responders eventually become resistant. Combination therapy is a rational strategy to increase response and tolerability of chemotherapeutic agents and to decrease resistance towards them. First-in-class small molecule clinical candidate ONC201 (also known as TIC10) has shown remarkable activity in several difficult to treat cancers. In the present study, we show that ONC201 exhibits synergism when combined with doxorubicin (Dox) against TNBC cell lines. At the end of treatment, Dox+ONC201-treated samples showed enhanced decrease in cell viability as compared to single drug controls. We observed that ONC201 was able to rescue MDA MB 231 cells from Dox-induced G2-M arrest and senescence as observed by cell cycle analysis using flow cytometry. Gene expression analysis using qRT-PCR indicated that, though ONC201 alone did not upregulate expression of its key target genes such as death receptor 5 (DR5), ATF-4 and caseinolytic protease (cIpP), it downregulated Dox-induced p21 expression (a hallmark of Dox-induced senescence) in the Dox+ONC201-treated MDA MB 231. Further, when cells were allowed to recover after drug treatment, viable fraction of Dox-treated samples continued to show senescent morphology, while these senescent cells were not observed in Dox+ONC201-treated samples. Overall, this study indicates that ONC201 shows synergistic response when combined with Dox against TNBC cells and may exhibit senolytic properties.
Audience Take Away Notes:
- Usually, selection of drugs for combination therapy and demonstration of the clinical benefit is done by trial and error, and therefore is time consuming and inefficient. This preclinical in vitro study to assess efficacy of drug combination and its mechanism of action provides proof-of-concept for focused potential clinical trials and consequently, for tailoring therapies to improve outcome for aggressive TNBCs.
