ABSTRACT Background Although TP53 and RB1 co‐alterations play critical roles in promoting malignant development and progression, specific inhibitors targeting this co‐alteration are lacking. We performed a pan‐cancer analysis to characterize the biology of TP53 / RB1 co‐alterations and identify therapeutic strategies. Methods We analyzed mutation data and copy number variation (CNV) data from 42 371 pan‐cancer samples across 26 cancer types from the cBioPortal database. Among them, 2417 tumors with TP53 / RB1 co‐alterations were used for further analysis. We characterized their epidemiology and molecular biology. Therapeutic vulnerabilities of co‐altered tumors were examined using Cancer Cell Line Encyclopedia drug screening datasets. Results TP53 / RB1 co‐alterations occurred in 5.70% of pan‐cancer cases but exhibit striking heterogeneity across cancer types. Patients harboring co‐alterations had significantly shorter overall survival (OS) in both primary and metastatic settings and poorer response to immune checkpoint inhibitors. Co‐altered tumors displayed frequent alterations in chromatin remodeling genes ( CREBBP , ARID1A , and KMT2D ) and PI3K pathway ( PIK3CA and PTEN ), but with distinct tissue‐specific mutational patterns: EGFR mutations dominated in lung adenocarcinoma (52%), KRAS in pancreatic cancer (88%), and APC in colorectal cancer (77%). Moreover, upregulated genes in co‐altered tumors enriched in cell cycle pathways, DNA repair, and neuronal development, whereas immune/inflammatory signaling was suppressed. Critically, drug screening revealed that co‐altered tumors showed increased sensitivity to CDK, AURKA, and PI3K/mTOR inhibitors, but resistance to MAPK/ERK pathway inhibitors. Conclusions TP53 / RB1 co‐alterations define an aggressive cancer subset with dysregulated cell cycle/chromatin pathways and reduced immunotherapy response. Targeting CDK, AURKA, or PI3K signaling offers promising therapeutic strategies.
Li et al. (2026) studied this question.