Fig. 1: The MAPK pathway is hyperactive and an oncogenic dependency in MPM. | Cell Death Discovery

Fig. 1: The MAPK pathway is hyperactive and an oncogenic dependency in MPM.

From: MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma

Fig. 1

A p-MEK1 (Ser217/221) protein levels in The Cancer Genome Atlas (TCGA) pan-cancer cohort (n = 32). The protein expression profile [reverse-phase protein array (RPPA)] was downloaded from The Cancer Proteome Atlas (TCPA) portal (https://tcpaportal.org/). The x-axis represents the cancer types and is ordered by mean p-MEK1 (Ser217/221) protein level. B Genetic alterations of tumor suppressor genes (TSG) in the TCGA cohort of malignant pleural mesothelioma (MPM) patients (n = 83). Data were downloaded from the cBioPortal for Cancer Genomics (https://www.cbioportal.org/). The blue color represents homozygous deletion of the indicated genes, while the red color indicates point mutations. C Histogram plots showing the difference in p-MEK1 protein levels between MPM samples from a cohort of patients in TCGA stratified by the indicated mutations. Notably, the p-MEK1 protein levels are independent of the mutational status of TSGs (BAP1, NF2, TP53, and CDKN2A). The p-value was determined by Welch’s t-test. D p-MEK1 (Ser217/221) protein level is positively correlated with anti-apoptotic proteins (BCL2A1, BCL-XL) in MPM patients. Proteomic data of patient MPM tumors were downloaded from the TCPA database. E Immunoblots of a panel of MPM cells treated with siRNA-based MAP2K1 (encoding MEK1) knockdown. F Viability assay of the indicated MPM cells transfected (72 h) with MAP2K1-specific or control siRNAs. *p < 0.05, **p < 0.01, ***p < 0.001 by Welch’s t-test (n = 3). In MESO-1 cells, both MAP2K1 and MAP2K2 were knocked down by siRNAs. G Flow cytometry-based apoptotic analysis of MPM cells after 72 h transfection with MEK1-specific siRNAs (si-MEK1). The Q1 and Q2 populations (in red) are considered apoptotic cells. The percentage of early and late apoptotic cells, defined by Annexin V+/PI- and Annexin V+/PI+ populations, respectively, were highlighted in red. H In vivo efficacy of trametinib (0.25 mg/kg) in patient-derived xenograft (PDX) BE261T (5 mice/group). Data were shown as mean ± SEM, with ****p < 0.0001 by two-way ANOVA. I, J Kaplan–Meier univariate survival (H) and multivariate Cox regression (I) analyses of the TCGA cohort of MPM patients. Patients are dichotomized by the optimal cutoff value of MAP2K1 (n = 85) or the p-MEK1 (n = 61) level across all patients, with survival curves and cumulative hazard rates analyzed and plotted using the R ‘survival’ and ‘survminer’ packages. The p-value was calculated using the log-rank test.

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