Mutant p53 variants differentially impact replication initiation and activate cGAS-STING to affect immune checkpoint inhibition
Year: 2025
Type: article
Abstract: Prior research shows that Akt-dependent phosphorylation of TopBP1 in S phase results in the switch of TopBP1/Treslin binding to TopBP1/E2F1 binding, which is important to prevent replication re-initiation in late S and G2 phases. Here, we demonstrate that contact, but not conformational, mutant p53 can override this switch by binding to both TopBP1 and Treslin, thereby facilitating persistent TopBP1/Treslin interaction in late S and G2 phases, which ultimately leads to over-firing of replication initiation. This increases micronuclei formation, which is further enhanced by genotoxic stressors such as doxorubicin, PARP inhibitors, or ATR inhibitors. Consequently, contact mutant p53 increases the sensitivity of cancer cells to a TopBP1-BRCT7/8 inhibitor combined with PARP or ATR inhibitors. Importantly, contact mutant p53 induces micronuclei formation and MRE11 expression, thereby activating cGAS-STING pathway and enhancing response to immune checkpoint inhibition. This finding is validated in murine mammary tumor allografts and further corroborated by clinical data.
Source: Communications Biology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,190
Awards: G1640819147, 14-3-3tau drives estrogen receptor loss and breast cancer progression, G2362353597, EXPLOITING A NEW ACHILLES' HEEL OF MUTANT P53 IN BREAST CANCER, SYNTHETIC LETHAL COMBINATION TARGETING TOPBP1 AND ARACHIDONIC ACID PATHWAY IN BREAST CANCER., NOVEL SYNTHETIC LETHAL THERAPIES FOR TRIPLE-NEGATIVE BREAST CANCER, INDUCING BRCANESS TO SYNERGIZE WITH PARP INHIBITORS IN BREAST CANCER, G4119534169, New Therapeutics Targeting MYC and Immune Escape in Lung Cancer, Inducing BRCAness to Synergize with PARP Inhibitors in Breast Cancer, Novel therapeutics for targeting checkpoint dysfunction in cancer, NEW THERAPEUTICS TARGETING MYC AND IMMUNE ESCAPE IN LUNG CANCER, G5850682332, Exploiting a New Achilles' Heel of Mutant p53 in Breast Cancer, G6334175762, Novel Synthetic Lethal Therapies for Triple-Negative Breast Cancer, Synthetic Lethal Combination Targeting TopBP1 and Arachidonic Acid Pathway in Breast Cancer, G8078076234, G8166743225, G8181764636, G8450630105, G8535862458, G8768414249, G9000326326, Training Program in Cell and Molecular Biology
OpenAlex ID: W4415913536