Combination of PARP inhibitor and CDK4/6 inhibitor modulates cGAS/STING‐dependent therapy‐induced senescence and provides “one‐two punch” opportunity with anti‐PD‐L1 therapy in colorectal cancer

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.

The senescence journey in cancer immunoediting

“…A large body of evidence has described the upregulation of the immune checkpoint molecule PD-L1 [ 58 , 207 – 209 ] and PD-L2 [ 210 ] in SnCs leading to an impairment of T cell mediated immune response.…”

“…In this context, characterization of SASP components revealed the presence of type I IFNs and some interferon-stimulated genes (ISGs) like CCL5 and CXCL10 chemokines as result of the activation of cGAS/STING signaling pathway. The addition of the immune checkpoint inhibitor anti-PD-L1 further improved the clearance of senescent cancer cells in immunocompetent mice [ 209 ]. In a Trp53 WT mouse mammary tumor model, chemotherapy followed by treatment with anti-PD-L1, stimulated a substantial accumulation of T cells within the tumor and a concomitant anti-tumor immune response.…”