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Clonal Competition Assays Identify Fitness Signatures in Cancer Progression and Resistance in Multiple Myeloma

ABSTRACT: Multiple Myeloma is a genetically heterogeneous disease and the management of relapses is one of the biggest clinical challenges. TP53 alterations are established high-risk markers of MM and are included in the current disease staging criteria. KRAS is the most frequently mutated gene affecting around 20% of MM patients. Applying Clonal Competition Assays (CCA) co-culturing color-labeled genetically modified cell lines, we recently showed that both, mono- and biallelic single-point mutations in TP53 transmit a fitness advantage to the cells. Here we report a similar dynamic for two mutations in KRAS (G12A and A146T). The fitness benefit of TP53 and KRAS mutations was treatment-independent, unlike patient-derived drug resistance alterations that only induce an advantage when the drug is present. CUL4B KO and IKZF1 A152T, both previously confirmed to transmit resistance against immunomodulatory agents, as well as PSMB5 A20T, a mutation located in the binding site of proteasome inhibitors do not transfer a fitness advantage to the cells per se, rather a disadvantage in comparison to the wildtype cell line. They only outcompete the culture when the respective drug was applied. Thus, to prevent the selection of clones harboring the potential of inducing a relapse, these results argue in favor of treatment-free breaks or alternatively for a switch of the drug class given as maintenance therapy. Furthermore, our data gives a biological rationale for the high frequency of KRAS and TP53 alterations at MM relapse. CCAs are suitable models for the study of clonal evolution and competitive (dis)advantages conveyed by a specific genetic lesion of interest, in dependence on external factors such as the treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247219 | GEO | 2024/07/17

REPOSITORIES: GEO

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Project description:The success of targeted therapies creates a need to discriminate tumors accurately by their histological and genetic characteristics. Here, we used cDNA microarray analysis to identify gene expression profiles and single markers that recapitulate the pathological and genetic background (i.e., BRAF, EGFR, KRAS, LKB1, PIK3CA, and TP53 gene alterations) of non-small cell lung cancer (NSCLC). Gene expression profiles were determined for 6 normal lung tissues and 69 lung tumors from patients diagnosed with NSCLC. We performed an unsupervised hierarchical clustering with the most variably expressed transcript to investigate whether there was evidence for natural grouping samples based on similarity in gene expression profiles. We examined the relationship between the clusters of tumors and patient and tumor characteristics such as gender, smoking status, histological type, degree of differentiation, tumor size, lymph node involvement and genetic background. We used a supervised analysis to identify the genes that are important for distinguishing subgroups of tumors defined by histological type. Moreover, we used this supervised approach to search for markers that characterize those tumors carrying EGFR, KRAS, PIK3CA and TP53 alterations. We identify several genes with characteristic patterns of expression in each tumor histological type (adenocarcinoma and squamous cell carcinoma) and we found that the presence of EGFR mutations result in a particular expression profile. Keywords: Transciption profiling of tumors with different histological and genetic background. We analyzed 69 NSCLC tumors. All the samples were characterized by histological type and by the presence of alterations at genes that are known to be involved in lung carcinogenesis. Mutational analysis of BRAF, EGFR, KRAS, and LKB1 is provided only for adenocarcinomas and analysis of alterations at PIK3CA gene (mutational analysis or gene amplification by FISH analysis) is provided only for 47 of the tumors. We analyzed gene expression profiles to identify those genes that are differentially expressed between two subgroups by t-test: 1) adenocarcinomas vs. squamous cell carcinomas; 2) tumors with mutation at EGFR gene vs. wild type tumors; 3) tumors with mutation at KRAS gene vs. wild type tumors; 4) tumors with mutation at TP53 gene vs. wild type tumors; 5) tumors with alterations (mutation or gene amplification) at PIK3CA gene vs. wild type tumors.

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Clonal Competition Assays Identify Fitness Signatures in Cancer Progression and Resistance in Multiple Myeloma

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