p53 mutations define the chromatin landscape to confer drug tolerance in pancreatic cancer

Abstract

Somatic inactivation of p53 (TP53) mainly occurs as missense mutations that lead to the acquisition of neomorphic mutant protein forms. p53 mutants have been postulated to exert gain-of-function (GOF) effects, including promotion of metastasis and drug tolerance, which generally contribute to the acquisition of the lethal phenotype. Here, by integrating a p53 R270H -dependent transcriptomic analysis with chromatin accessibility (ATAC-seq) profiling, we shed light on the molecular basis of a p53 mutant-dependent drug-tolerant phenotype in pancreatic cancer. p53 R270H finely tunes chromatin accessibility in specific genomic loci, orchestrating a transcriptional programme that participates in phenotypic evolution of the cancer. We specifically focused on the p53 R270H -dependent regulation of the tyrosine kinase receptor macrophage-stimulating protein receptor (MST1r). MST1r deregulation substantially impinged on drug response in the experimental model, recapitulating the p53 R270H -dependent phenotype, and strongly correlated with p53 mutant and aggressive phenotype in pancreatic cancer patients. As cellular plasticity in the final stages of the evolution of pancreatic cancer seems to predominantly originate from epigenetic mechanisms, we propose that mutant p53 participates in the acquisition of a lethal phenotype by fine-tuning the chromatin landscape.

Programmed Cell Death Pathways in Cholangiocarcinoma: Opportunities for Targeted Therapy

“…Personalized medicine approaches [202][203][204][205][206][207][208][209][210], such as genomic profiling and the identification of biomarkers, may help to identify specific vulnerabilities in CCA cells and guide the selection of optimal therapeutic agents capable of modulating the cell death programs. In this scenario, mutations in TP53 [143,[211][212][213][214] and KRAS genes have been associated with poor prognosis and resistance to chemotherapy, while mutations in IDH1 and FGFR2 genes may predict responses to targeted therapies.…”

p53 regulates expression of nuclear envelope components in cancer cells

“…These hallmarks strongly overlap with the transformation process, and the loss of p53 recapitulate in part the effect of the mutation in lamin-coding genes on nuclear metabolism. Furthermore, p53 depletion or mutation might predispose the cell to undergo genomic instability and hence contributing to the cancer evolution [22,36,42,51]. Future work will be required for a comprehensive dissection of p53-nucleus interplay to better define a druggable approach model in the context of human disease and cancer pathogenesis [1], Dal [11].…”

Targeting drug‐tolerant cells: A promising strategy for overcoming acquired drug resistance in cancer cells

“…Structural alterations in the chromatin may induce remodeling of enhancers or super‐enhancers, which regulates the transcriptional programs, thereby affecting transcription. 159 , 160 Epigenetic readers, such as bromodomain and extraterminal (BET) proteins, have been reported to promote transcriptional adaptation and chromatin remodeling that are essential for establishing a DT state under some circumstances. For example, BET proteins facilitate chromatin responses to PI3K and MEK inhibitors in BC models, whereas JQ1, a BET inhibitor, has an opposite effect.…”