SHP2-Mediated Inhibition of DNA Repair Contributes to cGAS–STING Activation and Chemotherapeutic Sensitivity in Colon Cancer

Abstract

As a cytoplasmic sensor of double-stranded DNA (dsDNA), the cyclic GMP-AMP synthase–stimulator of IFN genes (STING) pathway plays an important role in antitumor immunity. In this study, we investigated the effect of Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) on tumor cell–intrinsic STING pathway activity and DNA repair in colon cancer. SHP2 interacted with and dephosphorylated PARP1 after DNA damage. PARP1 inhibition by SHP2 resulted in reduced DNA repair and accumulation of dsDNA in cells, thus promoting hyperactivation of the STING pathway. The SHP2 agonist lovastatin was able to enhance SHP2 activity and promote STING pathway activation. Moreover, lovastatin significantly enhanced the efficacy of chemotherapy in colon cancer models, in part via STING pathway-mediated antitumor immunity. These findings suggest that SHP2 exacerbates STING pathway activation by restricting PARP1-mediated DNA repair in tumor cells, providing a basis for the combined use of lovastatin and chemotherapy in the treatment of colon cancer. Significance: Dephosphorylation of PARP1 by SHP2 simultaneously suppresses DNA repair and enhances STING pathway-mediated antitumor immunity, highlighting SHP2 activation as a potential therapeutic approach in colon cancer.

cGAS–STING signaling pathway in gastrointestinal inflammatory disease and cancers

“…SHP2 agonist lovastatin increased chemosensitivity of colon cancer partly via the STING signaling pathway (Table 2). 108 …”

“…SHP2 agonist lovastatin increased chemosensitivity of colon cancer partly via the STING signaling pathway (Table 2). 108 T cells mediated immune response is essential for controlling and eradicating tumor cells. Increasing evidence indicates that cGAS-STING signaling pathway plays a critical role in anti-tumor immunity by modulating T-cell action.…”

“…Radiotherapy or chemotherapy drugs such as 5‐FU or CPT‐11 for colorectal cancer treatment can induce micronuclei formation and DSBs, thus triggering the cGAS–STING signaling pathway to exert anti‐tumor effects 98,108,117,119 98 .…”

“…Radiotherapy or chemotherapy drugs such as 5-FU or CPT-11 for colorectal cancer treatment can induce micronuclei formation and DSBs, thus triggering the cGAS-STING signaling pathway to exert anti-tumor effects. 98,108,117,119 Micronuclei-like DNA structures increased upon 5-FU treatment and the efficacy of 5-FU to reduce tumor burden in murine colorectal cancer models was dependent on STING-mediated anti-tumor immunity. 98 Antilipemic agent lovastatin, served as SHP2 agonist, enhanced the sensitivity of colorectal cancer to DNA damaging drug CPT-11.…”

“…Exploration of the molecular mechanism indicated that SHP2 inhibited DNA damage repair via dephosphorylating PARP1, thus activating cGAS–STING signaling pathway (Table 3). 108 Therefore, activating cGAS–STING signaling pathway may amplify the efficacy of chemotherapy drugs such as CPT‐11. However, it is worth noting that overactive cGAS–STING signaling pathway may contribute to CPT‐11‐induced intestinal mucositis, which is one of the most debilitating side‐effects of the drug 119 .…”