KRAS-SOS-1 Inhibition as New Pharmacological Target to Counteract Anaplastic Thyroid Carcinoma (ATC)
Anaplastic thyroid carcinoma (ATC) is the most aggressive and lethal form of thyroid cancer. Tumor cells in ATC often activate alternative signaling pathways, contributing to treatment resistance. A key protein implicated in the progression of ATC is the proto-oncogene KRAS, a member of the small guanosine triphosphate (GTP)-binding protein family. Although KRAS plays a critical role in cancer development and malignancy, it has traditionally been considered non-druggable and has not been previously investigated in the context of ATC.
A newly developed synthetic compound, BAY-293, specifically targets and inhibits the interaction between KRAS and the guanine nucleotide exchange factor SOS-1. This study aimed to evaluate, for the first time, the antitumor potential of BAY-293 using both in vitro and in vivo models of ATC.
The in vitro experiments employed various thyroid cancer cell lines to assess the impact of BAY-293 on key cellular processes including the modulation of the mitogen-activated protein kinase (MAPK) signaling pathway, induction of apoptosis, and inhibition of cell migration. To complement the in vitro findings and replicate the complex tumor microenvironment more accurately, an orthotopic in vivo model of ATC was utilized.
Results demonstrated that BAY-293 effectively disrupted the KRAS/MAPK/ERK signaling axis and downregulated β-catenin expression, both of which are crucial downstream mediators involved in cell migration and tumor progression. Additionally, BAY-293 promoted apoptotic activity, contributing to a reduction in tumor advancement in both in vitro and in vivo settings.
In summary, this study provides the first evidence supporting the therapeutic potential of targeting the KRAS/SOS-1 interaction in ATC. BAY-293 emerged as a promising compound capable of inhibiting critical pathways involved in tumor growth and migration. Further research is warranted to fully explore and validate the clinical relevance of BAY-293 and KRAS/SOS-1 inhibition in the treatment of thyroid cancer.