β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models

Abstract

Colorectal carcinomas (CRC) harbor well-defined genetic abnormalities including aberrant activation of Wnt/β-catenin and MAPK pathways, often simultaneously. While the MAPK pathway can be targeted using potent small molecule drugs, including BRAF and MEK inhibitors, β-catenin inhibition has been historically challenging. RNA interference (RNAi) approaches have advanced to the stage of clinical viability, and are especially well-suited for transcriptional modulators such as β-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacological agents. Using a recently-described tumor-selective nanoparticle containing a β-catenin-targeting RNAi trigger, in combination with the FDA-approved MEK inhibitor (MEKi) trametinib, we demonstrate synergistic tumor growth inhibition in in vivo models of CRC, melanoma and hepatocellular carcinoma. At dose levels which were insufficient to significantly impact tumor growth as monotherapies, combination regimens resulted in synergistic efficacy and complete tumor growth inhibition. Importantly, dual MEKi/RNAi therapy dramatically improved survival of mice bearing CRC liver metastases. In addition, pharmacological silencing of β-catenin mRNA was effective against tumors which are inherently resistant or which acquire drug-induced resistance to trametinib. These results provide a strong rationale for clinical evaluation of this dual-targeting approach for cancers harboring Wnt/β-catenin and MAPK pathway mutations.

POU4F1 promotes the resistance of melanoma to BRAF inhibitors through MEK/ERK pathway activation and MITF up-regulation

“…Cadherin-associated protein beta 1 (β-catenin) is another known transcription factor that regulates the expression of MITF 43 . Previous studies have found that β-catenin contributes to the formation of BRAFi resistance in melanoma, which, however, is independent on its downstream canonical Wnt-signaling pathway 44,45 . Given that β-catenin could facilitate the proliferation and metastasis of melanoma in an MITF-dependent manner, MITF probably mediates the effect of β-catenin on BRAFi therapy in melanoma patients.…”

Functional significance of Hippo/YAP signaling for drug resistance in colorectal cancer

“…Resistance to 5‐FU in CRC is a major clinical problem. While there are a number of mechanisms reported to be responsible for drug resistance, activation of several tissue polarity regulation pathways is quite appealing . Like wnt, notch, and hedgehog signaling pathways, YAP1 is an important regulator for embryonic development, organ size, cell differentiation, and cancer development .…”

Comment on: Food for Bone: Evidence for a Role for Delta-Tocotrienol in the Physiological Control of Osteoblast Migration. Int. J. Mol. Sci. 2020, 21, 4661

“…We recommend the authors to assess the effects of procaine on glycogen synthase kinase-3β expression and/or β-catenin phosphorylation or nuclear translocation, with or without the δ-TT. An established Wnt/β-catenin inhibitor (reviewed in [17]) or gene silencing [18] would be more conclusive approaches in determining the role of Wnt/β-catenin in mediating the δ-TT on MC3T3 cells.…”