P53 partial loss-of-function mutations sensitize to chemotherapy

Boris Klimovich,Nastasja Merle,Oleg Timofeev,Marco Mernberger,Michelle Neumann,Andrea Nist,Albrecht Stenzinger,Thorsten Stiewe,Daniel Kazdal,Sabrina Elmshäuser

doi:10.1038/s41388-021-02141-5

Abstract

The tumor suppressive transcription factor p53 is frequently inactivated in cancer cells by missense mutations that cluster in the DNA binding domain. 30% hit mutational hotspot residues, resulting in a complete loss of transcriptional activity and mutant p53-driven chemotherapy resistance. Of the remaining 70% of non-hotspot mutants, many are partial loss-of-function (partial-LOF) mutants with residual transcriptional activity. The therapeutic consequences of a partial-LOF have remained largely elusive. Using a p53 mutation engineered to reduce DNA binding, we demonstrate that partial-LOF is sufficient to enhance oncogene-driven tumorigenesis in mouse models of lung and pancreatic ductal adenocarcinoma and acute myeloid leukemia. Interestingly, mouse and human tumors with partial-LOF mutations showed mutant p53 protein accumulation similar as known for hotspot mutants. Different from the chemotherapy resistance caused by p53-loss, the partial-LOF mutant sensitized to an apoptotic chemotherapy response and led to a survival benefit. Mechanistically, the pro-apoptotic transcriptional activity of mouse and human partial-LOF mutants was rescued at high mutant protein levels, suggesting that accumulation of partial-LOF mutants enables the observed apoptotic chemotherapy response. p53 non-hotspot mutants with partial-LOF, therefore, represent tumorigenic p53 mutations that need to be distinguished from other mutations because of their beneficial impact on survival in a therapy context.

Highlights

The tumor suppressor gene TP53 is mutated in roughly half of all cancer patients [1]
P53 partial loss-of-function cooperates with Ras in leukemogenesis Having demonstrated efficient cooperation of the E177R partialLOF mutation with oncogenic Ras in two solid tumor models, we explored this cooperation in a model of acute myeloid leukemia (AML), which is driven by the combination of NrasG12D and AML1/ETO9a oncogenes and in which p53 is known to be tumor suppressive [37]
RNA-seq profiling of the E180R mutant demonstrated that its transcriptional activity is representative of the class of cooperativity mutants and validated this mouse strain as a suitable in vivo model for p53 partial-LOF mutations (Fig. 2)

Summary

Introduction

The tumor suppressor gene TP53 is mutated in roughly half of all cancer patients [1]. Several hotspot mutants have acquired neomorphic properties ( termed gain-of-function, GOF) that, in an oncogene-like fashion, actively promote tumor progression to a more aggressive and therapy-resistant state [6,7,8]. These properties of mutant p53 proteins help to explain the preference for missense over null mutations and the poor prognosis associated with p53 mutations in several cancer types [9]

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