MAP2K1 Mutation in Colorectal Cancer Patients: Therapeutic Challenge Using Patient-Derived Tumor Cell Lines

Abstract

BACKGROUND:The MAP2K1 K57T mutation is known to be a potential mechanism of primary and secondary resistance to EGFR inhibitors in metastatic colorectal cancer (CRC) and has also been reported to promote resistance to BRAF and MEK inhibitors. It is important to overcome therapeutic resistance to EGFR inhibitors to improve the treatment outcomes of metastatic CRC.METHODS: We established patient-derived tumor cells (PDCs) from metastatic lesions that newly appeared during treatment with a BRAF inhibitor (LGX-818) plus an EGFR inhibitor (cetuximab) in a patient with BRAF-mutant CRC. To investigate therapeutic options to overcome acquired resistance due to MAP2K1 mutation in BRAF-mutant CRC, we performed cell viability assays using the PDCs.RESULTS:We tested whether the PDCs were resistant to an EGFR inhibitor (cetuximab) and a BRAF inhibitor (sorafenib) as these cells were established at the time of resistance to the EGFR plus BRAF inhibitors. Moreover, the anti-tumor effect of AZD6244 (MEK inhibitor) was evaluated because PDCs harbored a MAP2K1 mutation at the time of resistance to the EGFR plus BRAF inhibitors. MTT proliferation assays showed that monotherapy with cetuximab, sorafenib, or AZD6244 did not suppress cell viability. We next tested viability of the PDCs to combination treatment with cetuximab plus AZD6244 and sorafenib plus AZD6244. Proliferation of PDCs was significantly inhibited by sorafenib and AZD6244, but not by cetuximab plus AZD6244. Investigation of the combined effect of sorafenib and AZD6244 using the calculated combination index (CI) showed synergistic effects of sorafenib and AZD6244 in combination therapy applied to PDCs with the MAP2K1 K57T mutation.CONCLUSION:Our results suggest that combination treatment with BRAF and MEK inhibitors might be a novel treatment strategy for MAP2K1 K57T-mutant CRC. This finding will be helpful to guide treatment of patients with CRC that is resistant to EGFR inhibitors.

MAP2K1 is a potential therapeutic target in erlotinib resistant head and neck squamous cell carcinoma

“…MAP2K1 p.K57 mutation is frequently observed in acquired resistance following EGFR blockade therapies 16–18 . Thus, targeting MAP2K1 in tumors has been proposed as a potential therapeutic strategy to overcome acquired resistance in colorectal cancer 19 .

Figure 4Genomic and proteomic alterations in SCC-R cells: ( a ) Copy number alterations (CNAs) of genes and their protein expression in SCC-R cells compared to SCC-S cells. Amplification and protein overexpression of ( b ) YAP1 and ( c ) AHRGEF1.

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A Brief Overview and Update on Major Molecular Genomic Alterations in Solid, Bone and Soft Tissue Tumors, and Hematopoietic As Well As Lymphoid Malignancies

“…While the rearranged during transfection gene (RET) was mutated in approximately 80% of medullary thyroid cancers, its fusions have been detected in papillary thyroid carcinoma, NSCLC, and a range of other tumor types at lower frequencies (Table 1). [41][42][43][44] The RET fusions in NSCLC were enriched in nonsmokers lacking other known driver mutations 45,46 and defined a new therapeutic target in this subset of lung cancers, especially with the availability of selective RET inhibitor selpercatinib, which demonstrated durable response and increased progression-free survival. 47,48 The FDA has approved Retevmo (selpercatinib, Eli Lilly and Company) for treating RET fusion-positive NSCLC, RET fusion-positive thyroid cancer, and RETmutant medullary thyroid cancer.…”

Genomics and Functional Genomics of Malignant Pleural Mesothelioma

“…Significant molecular alterations affecting PI3K-Akt, Wnt, Hippo, mTOR, PDGF (platelet-derived growth factor), and FGF (fibroblast growth factor) signaling pathways are also described [ 23 , 25 , 59 ]. Included among the mutated genes in these pathways are APC , ARID1A , BMPR1A , CHEK2 , DVL1 , EPHB1 , FBXW7 , KDR , MAP2K1 , PDGFRA , PTEN , RB1 , SMARCA4 , SMARCB1 , HRAS , NRAS , and WRN [ 23 , 24 , 59 , 70 , 76 , 77 ], whose genetic alterations have also been found in lung adenocarcinomas [ 78 , 79 , 80 ], colorectal [ 81 , 82 , 83 , 84 ], and breast cancers [ 85 ]. Moreover, oncogenic mutations in ABL1 , EP300 , PIK3CA , PIK3C2B , PTPN11 , and SETDB1 genes [ 23 , 24 , 25 , 59 , 62 ], and novel gains in regions encompassing RHEB , KDM5A , AXIN2 , RICTOR , TRIO , and DVL1 genes were identified [ 24 , 65 ].…”