A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types

Abstract

KRAS- and BRAF-mutant tumors are often dependent on MAPK signaling for proliferation and survival and thus sensitive to MAPK pathway inhibitors. However, clinical studies have shown that MEK inhibitors are not uniformly effective in these cancers indicating that mutational status of these oncogenes does not accurately capture MAPK pathway activity. A number of transcripts are regulated by this pathway and are recurrently identified in genome-based MAPK transcriptional signatures. To test whether the transcriptional output of only 10 of these targets could quantify MAPK pathway activity with potential predictive or prognostic clinical utility, we created a MAPK Pathway Activity Score (MPAS) derived from aggregated gene expression. In vitro, MPAS predicted sensitivity to MAPK inhibitors in multiple cell lines, comparable to or better than larger genome-based statistical models. Bridging in vitro studies and clinical samples, median MPAS from a given tumor type correlated with cobimetinib (MEK inhibitor) sensitivity of cancer cell lines originating from the same tissue type. Retrospective analyses of clinical datasets showed that MPAS was associated with the sensitivity of melanomas to vemurafenib (HR: 0.596) and negatively prognostic of overall or progression-free survival in both adjuvant and metastatic CRC (HR: 1.5 and 1.4), adrenal cancer (HR: 1.7), and HER2+ breast cancer (HR: 1.6). MPAS thus demonstrates potential clinical utility that warrants further exploration.

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

“…A range of genetic mutations have been identified as causing acquired BRAF resistance (recently reviewed by Tian and Guo and summarized in Table 1 ) [ 11 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ...…”

“…The multiplicity of potential targets raises the possibility of using genomic and proteomic data to personalize combination therapy towards the specific pathway that is activated during BRAF inhibitor resistance in individual patients with melanoma [ 211 ]. Investigators are developing an MAPK pathway activity score from aggregated gene expression data that could help to determine the best drug combination to use [ 64 ], but further validation is needed.…”

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

“…3B). To additionally confirm MEK1/2 signaling changes, we evaluated expression of 10 genes (PHLDA1, SPRY2, SPRY4, DUSP4, DUSP6, CCND1, EPHA2, EPHA4, ETV4, ETV5, see Table S3 for details) that were reported to reflect MEK1/2 activity [43]. We detected at least a two-fold increase in PHLDA1, SPRY2, DUSP4, DUSP6, and EPHA2 expression in cisplatin-resistant cells (Fig.…”

BRAF-Mutant Transcriptional Subtypes Predict Outcome of Combined BRAF, MEK, and EGFR Blockade with Dabrafenib, Trametinib, and Panitumumab in Patients with Colorectal Cancer

“…S1). In addition, significant suppression of MAPK activity, as measured by MAPK pathway activity score (MPAS) gene signature expression (17), was also observed in the on-treatment samples taken from both BM1 and BM2 patients treated with D+T+P ( Supplementary Fig. S2).…”

“…The hallmark KRAS signature 5953, previously shown to be upregulated in BM1 relative to BM2, includes the DUSP6, SPRY2, ETV4, and ETV5 genes, all of which predict sensitivity to MEK inhibition (19,20). We thus applied the parsimonious MPAS gene signature-which has been previously used in CRC (17) and contains the CCND1, DUSP4, DUSP6, ETV4, ETV5, NT5E, SPRY2, and SPRY4 genes-to our sample set but found no difference in baseline expression between BM1 and BM2 and no association with clinical outcome regardless of BM subtype (Supplementary Fig. S3B).…”