Patients suffering from cutaneous melanoma may soon have the option of being treated with novel therapies that specifically target certain genes, such as ERBB2, KIT, FGFR3, and RET. While at the moment they are considered atypical candidates for this type of melanoma, a recent study shines new light on the mechanisms involved and looks to make them relevant marks.
While there are several drug inhibitors for the BRAF/MEK combination for cases of BRAF activation at position 600, patients with melanomas that present oncogenic genetic aberrations don’t have any similar choices of effective signaling pathway blockers. Furthermore, those who respond to BRAF/MEK inhibitors typically develop treatment-resistance within 9 months to a year.
A team of researchers from the University of Würzburg, Germany, has examined 45 primary melanomas and 91 metastatic melanomas from 92 patients and compared them to a self-designed melanoma panel. This reference database contains more than 50 genes of the most relevant genetic alterations in melanoma and genes that affect signaling pathways.
The procedure allowed them to detect actionable somatic mutations, copy number variations (CNVs), and germline variants. Overall, CNVs were noticed in 30% of samples and contained amplifications of druggable kinases, such as CDK4, ERBB2, and KIT.
“The combination of CNVs with activating or deleterious mutations enabled us to create a pathway matrix, which illustrates the predicted activated signaling pathways for each patient”, explained DR. Silke Appenzeller.
Taking into account single nucleotide variants (SNVs) and CNVs, two-thirds of metastatic patients displayed co-occurring activations of at least two pathways. In 40% of cases, alterations in the CDK4 pathway were observed. Two-thirds of BRAF/NRAS wild-type melanomas were found to be harbor activating mutations or CNVs in receptor tyrosine kinases such as ERBB2 and KIT.
“We propose that a targeted, deep-sequencing approach with careful consideration of oncogenic and deleterious SNVs and CNVs will help to identify patients who might benefit from a combination of BRAF/MEK inhibitors with an individually determined “inhibitor X” from the very beginning of their treatment”.
Preclinical tests for dual-therapy regimens have already begun and results so far have been promising.
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