Summary
ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-independent dimers. RAF inhibitors effectively inhibit mutant monomers, but not dimers; their binding to one site in the dimer significantly reduces their affinity for the second. Tumors with non-V600E BRAF mutants are insensitive to these drugs and increased expression of BRAF V600E dimers causes acquired resistance. A compound that equally inhibits both sites of mutant RAF dimers inhibits tumors driven by either class of mutants or those BRAF V600E tumors with dimer-dependent acquired resistance to monomer-specific inhibitors.
Purpose
IFITM3, an interferon-inducible gene, is overexpressed in human colorectal cancer. In this study, we sought to determine the clinical significance and underlying mechanisms of its dysregulated expression in human colon tumor specimens and murine models of this disease.
Experimental Design
IFITM3 expression in a tissue microarray of tumor and matched normal colon tissue specimens and lymph node metastasis specimens obtained from 203 patients with colon cancer was measured immunohistochemically.
Results
IFITM3 was expressed at higher levels in colon tumors and, particularly, nodal metastases than in normal colon tissue. A Cox proportional hazards model showed that IFITM3 expression was an independent prognostic factor for disease-free survival in patients with colon cancer. Knockdown of IFITM3 expression by a specific small interfering RNA significantly suppressed the proliferation, colony formation, migration, and invasion of colon cancer cells in vitro and tumor growth and metastasis in a xenograft model. Restored expression of KLF4, a putative tumor suppressor, downregulated IFITM3 expression in colon cancer cells in vitro. Two KLF4-binding sites in the IFITM3 promoter bound specifically to KLF4 protein in a chromatin immunoprecipitation assay and promoter mutagenesis analyses. Specific deletion of KLF4 led to IFITM3 overexpression in colon mucosa in Villin-Cre+;Klf4fl/fl mice. An inverse correlation between loss of KLF4 expression and IFITM3 overexpression was evident in human colon tumors.
Conclusion
these clinical and mechanistic findings indicate that IFITM3 is a direct transcriptional target of KLF4 and that dysregulated KLF4 expression leads to aberrant IFITM3 expression, thus contributing to colon cancer progression and metastasis.
Translational relevanceHepatocyte growth factor (HGF) is involved in at least three important steps of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance in EGFR mutant lung cancer, inducing resistance to reversible EGFR-TKIs by restoring Met/Gab1/PI3K/Akt pathways, inducing resistance to next-generation EGFR-TKIs (irreversible TKI and mutant-selective EGFR-TKI), and accelerating the emergence of EGFR-TKI-resistant clones by continuous exposure to HGF. Therefore, HGF may be an ideal target for overcoming EGFR-TKI resistance in EGFR mutant lung cancer.
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