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In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53 -deficient lung adenocarcinoma, we found that Apc, Rb1 , or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2- the strongest drivers of growth in a KRAS-driven model-reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment. SIGNIFICANCE: By modeling complex genotypes in vivo , this study reveals key tumor suppressors that constrain the growth of EGFR -mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease. This article is highlighted in the In This Issue feature, p. 1601 ., (©2021 American Association for Cancer Research.)

Missense mutations in the TP53 gene produce mutant p53 (mutp53) proteins which may acquire oncogenic properties favoring chemoresistance, cell migration, and metastasis. The exploitation of cellular pathways that promote mutp53 degradation may reduce cell proliferation and invasion as well as increase the sensitivity to anticancer drugs, with a strong impact on current cancer therapies. In the last years, several molecules have been characterized for their ability to induce the degradation of mutp53 through the activation of autophagy. Here, we investigated the correlation between autophagy and mutp53 degradation induced by suberoylanilide hydroxamic acid (SAHA), an FDA-approved histone deacetylase inhibitor. In the human cancer lines MDA-MB-231 (mutp53-R280K) and DLD1 (mutp53-S241F), SAHA induced a significant mutp53 degradation. However, such degradation correlated with autophagy induction only in MDA-MB-231 cells, being counteracted by autophagy inhibition, which also increased SAHA-induced cell death. Conversely, in DLD1 cells SAHA triggered a low level of autophagy despite promoting a strong decrease in mutp53 level, and autophagy inhibition did not change either mutp53 levels or sensitivity to this drug. We conclude that autophagy can be a relevant pathway for mutp53 degradation induced by SAHA, but its contribution to mutp53 destabilization and the consequences on cell death are likely context-dependent., (© 2019 The Author(s).)

PRIMA-1 has been identified as a compound that restores the transactivation function to mutant p53 and induces apoptosis in cells expressing mutant p53. Studies on subcellular distribution of the mutant p53 protein upon treatment with PRIMA-1Met, a methylated form of PRIMA-1, have suggested that redistribution of mutant p53 to nucleoli may play a role in PRIMA-1 induced apoptosis. Here, we specifically investigated the influence of PRIMA-1 on cellular localization of mutated p53-R280K endogenously expressed in tumour cells. By using immunofluorescence staining, we found a strong nucleolar redistribution of mutant p53 following PRIMA-1 treatment. This subcellular localization was associated to p53 degradation via ubiquitylation. When cells were treated with adriamycin, neither nucleolar redistribution nor mutant p53 down modulation and degradation were observed. Interestingly, cells where p53-R280K was silenced were more sensitive to PRIMA-1 than the parental ones. These results indicate that in some cellular context, the cell sensitivity to PRIMA-1 could depend on the abolition of a gain-of-function activity of the mutated p53, through a protein degradation pathway specifically induced by this compound., (Copyright © 2010 Elsevier Inc. All rights reserved.)