Inhibition of therapy-resistant and metastatic melanoma by targeting the translation initiation complex.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The eIF4F translation initiation complex is upregulated in cancer, promoting oncogenic protein synthesis.
• SBI-756, a known inhibitor, targets eIF4F assembly and has shown efficacy in melanoma, pancreatic cancer, and lymphoma.
• Melanoma resistance to BRAF inhibitors is a significant clinical challenge.

Purpose of the Study:

• To identify the specific molecular target of SBI-756 within the eIF4F complex.
• To discover novel small molecule inhibitors targeting this domain for melanoma treatment.
• To evaluate the efficacy of these inhibitors in preclinical models, including resistant melanoma.

Main Methods:

• Structure-based in silico screening against the eIF4G1 MA3 domain.
• RNA sequencing (RNA-seq) and ribosome sequencing to analyze cellular responses.
• Preclinical studies using melanoma cell lines and xenograft models.
• Combination therapy studies with autophagy and histone deacetylase inhibitors.

Main Results:

• The eIF4G1 MA3 domain was identified as the direct target of SBI-756.
• A novel inhibitor, M19, was identified through in silico screening and showed anti-melanoma effects.
• M19-6 demonstrated significant anti-neoplastic activity, reduced melanoma growth and metastasis in vivo, and overcame resistance to BRAF/MEK inhibitors.
• UPR, mTOR, p53, and ROS signaling pathways were modulated by M19 treatment.
• Combination therapies with autophagy or HDAC inhibitors enhanced M19-6's anti-cancer effects.

Conclusions:

• The eIF4G1 MA3 domain is a druggable target for inhibiting melanoma progression.
• M19-6 represents a promising therapeutic candidate for overcoming melanoma resistance and treating metastatic disease.
• Targeting translation initiation offers a viable strategy for novel cancer therapies.