Associação Portuguesa de Investigação em Cancro
miRNAs increase the sensitivity of colon cancer cells to cetuximab therapy
miRNAs increase the sensitivity of colon cancer cells to cetuximab therapy
Investigators at the Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, from the research group headed by Cecília Rodrigues, discovered that restoration of two miRNAs commonly downregulated in colon tumors might constitute relevant candidates for future therapeutic intervention in combination with the monoclonal antibody cetuximab. The research was recently published in the journal Oncotarget.
Cancer cell resistance to chemotherapy and targeted therapeutic agents remains a major obstacle that impairs efficacy. In this context, miRNAs may provide a potential novel therapeutic approach. In this study, the authors have shown that modulation of miRNA-143 and miRNA-145 sensitizes colon cancer cells to cetuximab by stimulating cell death induced by cetuximab-mediated cellular cytotoxicity, independently of KRAS status. In addition, HCT116 colon cancer cells overexpressing these miRNAs triggered apoptosis in result of cetuximab-mediated cellular citotoxicity, effected by peripheral blood mononuclear cells.
The authors believe that the development of new miRNA-based therapeutic approaches could circumvent the resistance to targeted agents, and could ultimately translate into improved care for colon cancer patients.
Authors and Affiliations:
Sofia E. Gomes, André E. S. Simões, Diane M. Pereira, Rui E. Castro, Cecília M. P. Rodrigues, Pedro M. Borralho
Instituto de Investigação do medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa
Abstract:
miR-143 and miR-145 are downregulated in colon cancer. Here, we tested the effect of restoring these miRNAs on sensitization to cetuximab in mutant KRAS (HCT116 and SW480) and wild-type KRAS (SW48) colon cancer cells. We evaluated cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and the modulation of signaling pathways involved in immune effector cell-mediated elimination of cancer cells. Stable miR-143 or miR-145 overexpression increased cell sensitivity to cetuximab, resulting in a significant increase of cetuximab-mediated ADCC independently of KRAS status. Importantly, HCT116 cells overexpressing these miRNAs triggered apoptosis in result of cetuximab-mediated ADCC, effected by peripheral blood mononuclear cells (p < 0.01). This was associated with increased apoptosis and caspase-3/7 activity, and reduced Bcl-2 protein expression (p < 0.01). In addition, caspase inhibition abrogated cetuximab-mediated ADCC in HCT116 cells overexpressing either miR-143 or miR-145 (p < 0.01). Furthermore, Bcl-2 silencing led to high level of cetuximab-mediated ADCC, compared to control siRNA (p < 0.05). Importantly, granzyme B inhibition, abrogated cetuximab-mediated ADCC, reducing caspase-3/7 activity (p < 0.01). Collectively, our data suggests that re-introduction of miR-143 or miR-145 may provide a new approach for development of therapeutic strategies to re-sensitize colon cancer cells to cetuximab by stimulating cetuximab-dependent ADCC to induce cell death.
Journal: Oncotarget
