Abstract
The targeting of the Mitogen-Activated Protein Kinase (MAPK) signalling pathway in melanoma improves the prognosis of patients harbouring the V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) mutation. However, a fraction of these patients may experience tumour progression due to resistance to targeted therapy. Mutations affecting the Phosphoinositol-3-Kinase (PI3K)–Akt pathway may favour the onset of drug resistance, suggesting the existence of a crosstalk between the MAPK and PI3K–Akt pathways. We hypothesized that the inhibition of both pathways may be a therapeutic option in resistant melanoma. However, conflicting data have been generated in this context. In this study, three different A375 cell melanoma models either overexpressing or not expressing the wild-type or mutated form of the PhosphatidylInositol-4,5-bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) gene were used to clarify the therapeutic response of melanoma to BRAF, Mitogen-Activated Protein Kinase Kinase 1 (MEK), and PI3K inhibitors in the presence of the PIK3CA H1047R mutation. Our data strongly support the notion that the crosstalk between the MAPK and PI3K–Akt pathways is one of the main mechanisms associated with melanoma development and progression and that the combination of MAPK and PI3K inhibitors may sensitize melanoma cells to therapy.
Highlights
The targeting of the RAF–MEK–ERK pathway, known as the Mitogen-Activated Protein Kinase (MAPK) pathway, with the concomitant administration of V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) and Mitogen-Activated Protein Kinase Kinase 1 (MEK) inhibitors more effectively delays the emergence of adaptive and acquired resistance mechanisms compared with treatments with either BRAF or MEK inhibitors as single agents [7]
BRAF V600E is a dominant driver of mutations that are widely associated with melanoma aggressiveness [19], a small portion of resistant melanomas take advantage of the activation of the compensatory PI3K–Akt signalling cascade sustained by different genetic alterations
PI3K–Akt pathway (A375PIK3CA and A375H1047R ) showed a higher proliferation rate compared to that of A375pLNCX2, suggesting that the activation of the PI3K–Akt pathway is involved in melanoma progression. By treating these transduced cells with both BRAF and MEK inhibitors, we demonstrated that activation of the PI3K–Akt pathway mediated by the PIK3CA H1047R mutation confers drug resistance to dabrafenib and trametinib
Summary
The targeting of the Mitogen-Activated Protein Kinase (MAPK) signalling pathway in melanoma improves the prognosis of patients harbouring the V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) mutation. The high aggressiveness and metastatic power of melanoma as well as its resistance mechanisms to therapies are mediated by the overexpression of oncogenes and proteases that favour tumour invasiveness [4,5] and the overactivation of different signalling transduction pathways [6]. To effectively counteract these negative prognostic behaviours, novel therapeutic strategies are adopted.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
