DescriptionApoptosis is a canonical cellular death pathway that is inactivated in many human cancers. Functional studies have elucidated the signaling mechanisms that control apoptosis and have allowed for the development of novel therapeutics to reactivate apoptosis in cancer cells. Therapeutic induction of cell death often encounters resistance from other cellular survival pathways creating a requirement for combinatory therapeutics that simultaneously manipulate multiple cell death and survival pathways to kill tumor cells. Apoptosis is frequently blocked in cancer cells through overexpression of anti-apoptotic Bcl-2 family members. The small molecule ABT-737 binds Bcl-2, Bcl-xL, and Bcl-w with high affinity but not to less homologous Bfl1/A1 or Mcl-1. This leads to drug resistance in some tumor types. We have demonstrated that inhibition of Bcl-2 with ABT-737 is not sufficient to induce cell death in immortalized mouse prostate epithelial cell lines. Combinations of ABT-737 with DNA damaging agents that down regulate Mcl-1 expression induce cleavage of caspase-3 and cell death by apoptosis. Furthermore, we have established a novel tumor explant system, termed Tumor Tissue Assessment for Response to Chemotherapy (TTARC), to assess the effectiveness of drug combinations in human cancer tissue. TTARC demonstrated the efficacy of combining ABT-737 with the DNA damaging agent Cisplatin ex-vivo. Thus rational targeting of both Bcl-2 and Mcl-1 eliminated apoptosis resistance leading to cell death in prostate cancer. Rational targeting of multiple death and survival pathways is a treatment strategy that can be applied to a broad range of cancer types. Human renal cell carcinoma (RCC) is commonly treated with the mTOR inhibitor CCI-779. While CCI-779 improves overall survival of RCC patients, it is not curative. We have identified mitophagy as a resistance mechanism to mTOR inhibition. CCI-779 induced profound mitochondrial damage that resulted in metabolic stress and reactive oxygen species (ROS) production. Furthermore CCI-779 blocked the Nrf2 antioxidant response pathway contributing to ROS propagation. RCC cells eliminated damaged mitochondria through mitophagy enabling survival. Combining CCI-779 with the autophagy inhibitor chloroquine activated RIP kinases and necroptotic cell death. Taken together, this data suggests that thoughtful manipulation of cell death and survival pathways will lead to more effective treatment regimes.