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Mutant p53 gain-of-function impact is repressed in the presence of other major oncogenic drivers

ABSTRACT: Mutant TP53, mutant KRAS and hyperactive CMYC are driver oncogenes with no standard clinical protocols for their direct targeting. To identify interplay of mutant TP53, KRAS and hyperactive CMYC, and exploit them in a therapeutic manner, we performed global proteomics and transcriptomics in a panel of 8 cell lines of colorectal and lung cancers 48h post knock-out of the oncogenes with CRISPR/Cas9. In each cancer type the cell lines containing either all, or one, of each of the activated oncogenes were analyzed. Higher numbers of significant protein and transcript level changes were observed upon CMYC and KRAS disruption compared to mutant TP53 disruption. In contrast to mutant KRAS and CMYC downstream programs the number of mutant p53-dependent proteins and transcripts was reduced several-fold in the presence of mutant KRAS and hyperactive CMYC, compared to cell lines with mutant p53 only. We observed a functional repression of the mutant p53 ability to drive phenotype of cancer cells and transcriptional activity in the presence of mutated KRAS and/or overexpressed CMYC, which in such configuration overtake many of the mutant p53 functions. An overlap of pathways regulated by the transcripts and proteins revealed a molecular program shared by the oncogenes as well as pathways lost or retained in the mutant p53 program, when co-present with the other oncogenes. This allowed to exploit the program common to the oncogenes by experimental, pre-clinical drug targeting. Oncogene cooperation is known to be important in driving cell transformation, however our observations suggest that mutant KRAS and/or overexpressed CMYC compete with mutant p53 for activation of important oncogenic pathways. While the exact mechanism of this competition is under investigation, we hypothesize that mutant p53 is a context-dependent oncogene – whose gain-of-function range of impact heavily depends on the molecular background of neoplastic cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239817 | GEO | 2024/08/31

REPOSITORIES: GEO

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Project description:We have developed cdk4/hTERT-immortalized normal human bronchial epithelial cells (HBECs) to study lung cancer pathogenesis. By studying the oncogenic effect of common lung cancer alterations (p53, KRAS, and c-MYC) we demonstrate the ability of this model to characterize the stepwise transformation of bronchial epithelial cells to full malignancy. Using HBECs derived from multiple individuals we found: 1) the combination of five genetic alterations (p53, KRASV12, c-MYC, CDK4 and hTERT) is sufficient for full tumorigenic conversion of HBECs; 2) high levels of KRASV12 are required for full malignant transformation of HBECs, however these levels also stimulate oncogene-induced senescence; 3) RAS-induced senescence is largely bypassed with loss of p53 function; 4) over-expression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRASV12; 5) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; 6) serum-induced epithelial-to-mesenchymal transition (EMT) increases in vivo tumorigenicity; 7) genetically-identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation as well as sensitivity to standard platinum-based chemotherapies; and 8) an mRNA signature derived from tumorigenic and non-tumorigenic clones is predictive of outcome in lung cancer patients. Collectively, we demonstrate this HBEC model system can be used to study the effect of oncogenic mutations on malignant progression, oncogene-induced senescence, and EMT along with clinically translatable applications such as development of prognostic signatures and drug response phenotypes. Human bronchial epithelial cells (HBECs) immortalized with cdk4 and hTERT were transformed with p53 knockdown, KrasV12 and cMYC over-expression and profiled on Illumina HumanHT-12 V4.0 expression beadchips. Transformed HBECs were grown in two different growth media: KSFM (defined, serum-free medium) or R10 (RPMI with 10% FBS) as indicated. Clones were isolated from HBECs with sh-p53 + KrasV12 and sh-p53 + KrasV12 + cMYC.

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Mutant p53 gain-of-function impact is repressed in the presence of other major oncogenic drivers

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