Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation
Li Ren Kong, Richard Ong, Tuan Zea Tan, Nur Afiqah Binte Mohamed Salleh, Matan Thangavelu Thangavelu, Jane Vin Chan, Lie Yong Judice Koh, Giridharan Periyasamy, Jieying Amelia Lau, Thi Bich Uyen Le, Lingzhi Wang, Mi‐Young Lee, Srinivasaraghavan Kannan, Chandra Verma, Chwee Ming Lim, Wee Joo Chng, David P. Lane, Ashok R. Venkitaraman, Huynh The Hung, Chit Fang Cheok, Boon Cher Goh
Abstract
Abstract Gain of function (GOF) DNA binding domain (DBD) mutations of TP53 upregulate chromatin regulatory genes that promote genome-wide histone methylation and acetylation. Here, we therapeutically exploit the oncogenic GOF mechanisms of p53 codon 158 (Arg 158 ) mutation, a DBD mutant found to be prevalent in lung carcinomas. Using high throughput compound screening and combination analyses, we uncover that acetylating mutp53 R158G could render cancers susceptible to cisplatin-induced DNA stress. Acetylation of mutp53 R158G alters DNA binding motifs and upregulates TRAIP, a RING domain-containing E3 ubiquitin ligase which dephosphorylates IĸB and impedes nuclear translocation of RelA (p65), thus repressing oncogenic nuclear factor kappa-B (NF-ĸB) signaling and inducing apoptosis. Given that this mechanism of cytotoxic vulnerability appears inapt in p53 wild-type (WT) or other hotspot GOF mutp53 cells, our work provides a therapeutic opportunity specific to Arg 158 -mutp53 tumors utilizing a regimen consisting of DNA-damaging agents and mutp53 acetylators, which is currently being pursued clinically.