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. 2024 Jun 24;16(13):2313.
doi: 10.3390/cancers16132313.

Unsupervised Analysis Reveals the Involvement of Key Immune Response Genes and the Matrisome in Resistance to BRAF and MEK Inhibitors in Melanoma

Feng Liu-Smith  1   2 , Jianjian Lin  1
Affiliations

Unsupervised Analysis Reveals the Involvement of Key Immune Response Genes and the Matrisome in Resistance to BRAF and MEK Inhibitors in Melanoma

Feng Liu-Smith et al. Cancers (Basel). .

Abstract

Melanoma tumors exhibit a wide range of heterogeneity in genomics even with shared mutations in the MAPK pathway, including BRAF mutations. Consistently, adaptive drug resistance to BRAF inhibitors and/or BRAF plus MEK inhibitors also exhibits a wide range of heterogeneous responses, which poses an obstacle for discovering common genes and pathways that can be used in clinic for overcoming drug resistance. This study objectively analyzed two sets of previously published tumor genomics data comparing pre-treated melanoma tumors and BRAFi- and/or MEKi-resistant tumors. Heterogeneity in response to BRAFi and BRAFi/MEKi was evident because the pre-treated tumors and resistant tumors did not exhibit a tendency of clustering together. Differentially expressed gene (DEG) analysis revealed eight genes and two related enriched signature gene sets (matrisome and matrisome-associated signature gene sets) shared by both sets of data. The matrisome was closely related to the tumor microenvironment and immune response, and five out of the eight shared genes were also related to immune response. The PLXNC1 gene links the shared gene set and the enriched signature gene sets as it presented in all analysis results. As the PLXNC1 gene was up-regulated in the resistant tumors, we validated the up-regulation of this gene in a laboratory using vemurafenib-resistant cell lines. Given its role in promoting inflammation, this study suggests that resistant tumors exhibit an inflammatory tumor microenvironment. The involvement of the matrisome and the specific set of immune genes identified in this study may provide new opportunities for developing future therapeutic methods.

Keywords: PLXNC1; drug resistance; matrisome; melanoma; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Melanoma tumors and patients are not grouped by drug resistance. (a,b) Heatmap of gene expression in GSE50509 and GSE61992, respectively. In the “response” variable, NoRes, no response; PR, partial response; RES, response; SD, stable disease. Tumors are colored by “pretreatment” and “progression” (resistant tumors). (c,d) Principal component analysis of the two datasets based on patients and treatment. EDT: early during treatment when the tumors were excised. Some patients have multiple tumors, either from pre-treatment or progression.
Figure 2
Figure 2
PLXNC1 is up-regulated at an mRNA level in BRAFi-resistant melanoma cell lines. The qRT-PCR experiment was performed with GAPDH as an internal control, and the DDCt method was used to calculate the relative expression levels of the resistant cells normalized to the parental control cells.
See this image and copyright information in PMC

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