High Let-7a MicroRNA Levels in KRAS-Mutated Colorectal Carcinomas May Rescue Anti-EGFR Therapy Effects in Patients with Chemotherapy-Refractory Metastatic Disease

Abstract

Preclinical and experimental data in vivo indicate that Lethal-7 (Let-7) microRNA downregulates KRAS with antitumor effects in the presence of activating KRAS mutations. We quantified the Let-7a isoform in KRASmutated colorectal carcinomas from patients who received salvage cetuximab plus irinotecan. The study population was retrospectively identified among metastatic colorectal cancer patients who underwent third-line therapy with cetuximab plus irinotecan in a period when only epidermal growth factor receptor (EGFR) expression was required for anti-EGFR therapy. In 59 patients harboring KRAS mutations, Let-7a levels were analyzed for association with overall survival (OS) and progression-free survival (PFS) times. An exploratory subgroup analysis was performed using the rs61764370 (LCS6 T>G) polymorphism that experimentally impairs Let-7 binding to KRAS mRNA. In the whole group, higher Let-7a levels were significantly associated with better survival outcomes. For the primary OS endpoint, the multivariate hazard ratio was 0.82 (95% confidence interval, 0.73-0.91; p ‫؍‬ .01). The same findings with an accentuated positive effect of high Let-7a levels on both OS and PFS times were observed in an exploratory analysis of the 45 wild-type LCS6 patients (excluding 14 carriers of the LCS6 G allele variant). All survival associations were confirmed after excluding patients with KRAS codon 13 mutations. Among the clinicopathologic features, high Let-7a levels were associated with grade 2-3 skin toxicity (p ‫؍‬ .002). In patients with KRAS mutations, Let-7a analysis may serve to identify subgroups of patients who may still benefit from EGFR inhibition and this may open up new perspectives for alternative treatment strategies.

LIN-28B/let-7a/IGF-II axis molecular subtypes are associated with epithelial ovarian cancer prognosis

“…MicroRNA let-7a is one member of the let-7 family, which is wellcharacterized in fine-tuning gene expression, and plays important roles in cell proliferation, differentiation, apoptosis and metabolism [24]. Aberrant expression of let-7a has been reported in various types of human cancer [41], and is associated with cell proliferation, chemotherapy response, and patient survival [30,42]. Evidence suggests that let-7a may operate in favor of tumor progression in human tumors under certain conditions [7,30].…”

Colorectal cancer carcinogenesis: a review of mechanisms

“…These factors are important in predicting the response to particular therapies. MicroRNAs act as positive biomarkers indicating sensitivity to therapy or as negative biomarkers signifying resistance to treatment and assisting in choosing the appropriate treatment regimen (Table 1) [164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179] .…”

“…This difference also further enhances Wnt activity and may form a feedback loop as a downstream target of Wnt 191 . [164][165][166][167] MiR-126 ↓ Decreased sensitivity to capecitabine and oxaliplatin (XELOX) [168][169] MiR-31 ↑ Decreased sensitivity to 5-fluorouracil …”

Investigation of nonspecific cross-reacting antigen 2 as a prognostic biomarker in bone marrow plasma from colorectal cancer patients

“…One of the let-7a targets is KRAS and patients with KRAS mutations and high let-7a expression have shown increased survival benefit from anti-EGFR therapy [210,211]. Let-7a may therefore be a predictive biomarker for subgroups of patients receiving anti-EGFR therapy.…”