KIT M541L

NGS analysis of TETs revealed several somatic variants in genes related to the p53, AKT, MAPK, and K-Ras signalling pathways. TCs showed greater genetic dysregulation than TMs. KIT alterations in TCs have potential as therapeutic targets.

Results The NGS analysis showed similar results for melanoma cell lines A375 and A2058, with SNV genomic alteration of BRAF (V600E) as relevant biomarker targeted by kinase inhibitors (binimetinib + encorafenib; cobimetinib + vemurafenib; dabrafenib; dabrafenib + trametinib), but also indicator of checkpoint inhibitors uses (atezolizumab; ipilimumab + nivolumab) in combinatorial therapies. Nevertheless, SK-MEL-2 cell line had similar immunophenotypic profile, although the genomic alterations were totally different. Discussion For establishing the appropriate therapeutic approach in melanoma cases, the personalized treatment should be envisioned, based on both next generation sequencing, surface markers expression, as well as microenvironment assessment.

Results The NGS analysis showed similar results for melanoma cell lines A375 and A2058, with SNV genomic alteration of BRAF (V600E) as relevant biomarker targeted by kinase inhibitors (binimetinib + encorafenib; cobimetinib + vemurafenib; dabrafenib; dabrafenib + trametinib), but also indicator of checkpoint inhibitors uses (atezolizumab; ipilimumab + nivolumab) in combinatorial therapies. Nevertheless, SK-MEL-2 cell line had similar immunophenotypic profile, although the genomic alterations were totally different. Discussion For establishing the appropriate therapeutic approach in melanoma cases, the personalized treatment should be envisioned, based on both next generation sequencing, surface markers expression, as well as microenvironment assessment.

Moreover, 3D in vitro culture results suggested that M541L c-Kit somatic mutation could be a loss-of-function alteration by reducing HSC maintenance ability thus quickly promoting differentiation, as documented by in vivo graft failure and in vitro absence of long-term culture stability. In conclusions, our 3D BM-like biomimetic culture system allowed long-term stemness maintenance, making it a valid and effective tool for in vitro study of physiological and pathological hemopoiesis.

The germline and rare SNVs of uncertain clinical significance reported in this study add to the number of known genetic alterations in TETs, thus extending our molecular understanding of these neoplasms. Druggable KIT alterations in thymic carcinomas have potential as therapeutic targets.

Changes in protein trafficking and the glycocalyx composition of cancer cells may explain the observed alterations in galectin expression. This study can be useful for the targeted selection of receptor tyrosine kinase and galectin inhibitor anti-cancer treatments.

These data support the results of the GRID trial, and suggest that patients may benefit from regorafenib in the presence of KIT mutations and without the selection of particular mutation patterns that confer resistance. The study was not powered to address biomarker-related questions, and the results are exploratory and hypothesis-generating.

Complete surgical resection was not possible and leptomeningeal metastatic disease rapidly ensued despite immunotherapy. Further understanding of the molecular signature may translate to improved diagnosis, prognostication and development of targeted therapies.

This study highlights the role of single-nucleotide variants (SNVs) that may be considered non-pathogenic and suggests the prognostic significance for survival of KIT rs3822214 and KDR rs1870377 and potential importance in planning new treatment strategies for gliomas.