Changing The Guardian’s Playbook: Dissecting How Cancer Drivers Rewire p53 Gene Regulatory Networks

The tumor suppressor p53 is the most frequently mutated gene in cancer, and its inactivation enables progression from benign to malignant disease by disrupting transcriptional programs that actively constrain tumor progression. Using physiologically relevant murine and clinically derived models of pancreatobiliary cancer, we define molecular programs connecting p53 to tumor suppressive gene regulatory networks and identify rational strategies to reestablish p53 dependent therapeutic vulnerabilities. We demonstrate how mutations in isocitrate dehydrogenase (IDH) found in biliary cancer uncouple p53 activity from tumor suppression by perturbing chromatin landscapes imperative for p53-driven apoptosis. 2-hydroxyglutarate (2-HG) produced from IDH mutations inhibits alpha-ketoglutarate (αKG)-dependent chromatin remodelers required for p53 target gene regulation. Clinically relevant mutant IDH inhibitors reinvigorate latent tumor suppressive p53 outputs which we translate into a novel therapeutic strategy showing efficacy across models of biliary cancer. Mechanistically, αKG-sensitive chromatin regions opened by p53 activity display enrichment for YAP/TAZ-TEAD binding motifs, nominating this complex as a downstream transcriptional effector of p53 regulatory networks. p53 reshapes YAP/TAZ-TEAD genomic occupancy at newly accessible enhancers, generating distinct TEAD-driven regulons when p53 is engaged versus inactivated. During senescence, actin remodeling upregulates TAZ to potentiate TEAD coactivation of unique gene programs, including a TEAD-dependent arm of the senescence-associated secretory phenotype induced by both p53 activation and oncogene-targeted therapies. In addition, YAP/TAZ-TEAD compete with p53 to establish a gastric pit-like differentiation program reminiscent of metaplastic pancreas cells and the classical PDAC subtype. p53 and YAP/TAZ-TEAD activities inversely correlate with gastric/classical heterogeneity during PDAC development and modulation of both pathways determines gastric identity in vitro and in vivo. Competitive regulation of gastric differentiation by p53 and TEAD represents a therapeutically targetable determinant of PDAC plasticity with implications for new and existing treatments. Taken together, these findings reveal how cancer drivers co-opt transcriptional networks implicated in p53 tumor suppression, uncovering actionable mechanisms underlying cancer development that can be exploited for treating pancreatobiliary cancer, a patient population with high unmet clinical need.