Abstract 1054: Patient derived organoids demonstrate synergistic antitumor effect of senogenic and senolytic drug combination of Aurora kinase inhibitor and BCL2/xL inhibitor

Abstract

Abstract The management of metastatic melanoma continues to be challenging, despite of evolving treatments such as immune checkpoint blockade and inhibitors of mutated BRAF. New therapies that work via immune and BRAF-independent mechanisms are urgently required for tumors that are unresponsive to currently available treatments. Here we hypothesized that combination of Aurora Kinase inhibitor (AURKAi) alisertib (senescence inducer) with a drug that selectively kills senescent cells, such as BCL2/xL inhibitor (BCLi) navitoclax (senolytic), will induce apoptosis in melanoma cells. Patient derived organoids (PDOs) were used to test anti- tumor effect of AURKAi and BCLi combination treatment. H&E staining of PDOs and their matched original tumors revealed similar histology. Fourteen out of ninety PDOs were highly sensitive to AURKAi and BCLi combination treatment exhibiting robust induction of cell death. NextGen DNA sequencing indicated that all sensitive PDOs retained wild type TP53, while resistant tumors had mutations in this gene. Knockout or knockdown of TP53 abrogated AURKAi and BCLi-induced cell death in melanoma cells, suggesting that transcription factor p53 encoded by TP53 is a key mediator of drug response. Addition of BCLi to AURKAi activated proapoptotic p53 targets BAX, NOXA and induced cleavage of PARP and Caspases 3, 7, and 8. Electron microscopy revealed morphological signs of apoptosis in combination-treated cells, including cell blebbing, apoptotic bodies, and nuclear fragmentation. This suggests that BCLi shifts cell fate decision in AURKAi-treated cells towards apoptosis. In conclusion, combination treatment with AURKAi and BCl2i induced p53-dependent apoptosis. Preclinical evaluation of this drug combination in PDO model demonstrated robust efficacy against melanomas with wild type p53. Since p53 mutations are relatively rare in melanoma, combination of AURKAi and BCLi presents promising therapeutic option for this deadly disease. Keywords: Apoptosis, melanoma, patient-derived organoids, aurora kinase, bcl-2 Citation Format: Vijaya Bharti, Vivian Weiss, Chengli Shen, Sheau Chiann Chen, Ashlyn Blevins, Rebecca L. Shattuck-Brandt, Ann Richmond, Anna E. Vilgelm. Patient derived organoids demonstrate synergistic antitumor effect of senogenic and senolytic drug combination of Aurora kinase inhibitor and BCL2/xL inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1054.