Combination of <scp>PARP</scp> inhibitor and <scp>CDK4</scp>/6 inhibitor modulates <scp>cGAS</scp>/<scp>STING‐</scp>dependent therapy‐induced senescence and provides “one‐two punch” opportunity with <scp>anti‐PD‐L1</scp> therapy in colorectal cancer
Tao Wang, Weizhen Liu, Qian Shen, Ruikang Tao, Chengguo Li, Qian Shen, Yao Lin, Yongzhou Huang, Lei Yang, Gengchen Xie, Jie Bai, Ruidong Li, Lulu Wang, Kaixiong Tao, Yuping Yin
Abstract
Although PARP inhibitor (PARPi) has been proven to be a promising anticancer drug in cancer patients harboring BRCA1/2 mutation, it provides limited clinical benefit in colorectal cancer patients with a low prevalence of BRCA1/2 mutations. In our study, we found PARPi talazoparib significantly induced cellular senescence via inhibiting p53 ubiquitination and activating p21. Furthermore, CDK4/6i palbociclib amplified this therapy-induced senescence (TIS) in vitro and in vivo. Mechanistically, talazoparib and palbociclib combination induced senescence-associated secretory phenotype (SASP), and characterization of SASP components revealed type I interferon (IFN)-related mediators, which were amplified by cGAS/STING signaling. More importantly, RNA sequencing data indicated that combination therapy activated T cell signatures and combination treatment transformed the tumor microenvironment (TME) into a more antitumor state with increased CD8 T cells and natural killer (NK) cells and decreased macrophages and granulocytic myeloid-derived suppressor cells (G-MDSCs). Moreover, clearance of the TIS cells by αPD-L1 promoted survival in immunocompetent mouse colorectal cancer models. Collectively, we elucidated the synergistic antitumor and immunomodulatory mechanisms of the talazoparib-palbociclib combination. Further combination with PD-L1 antibody might be a promising "one-two punch" therapeutic strategy for colorectal cancer patients.