Targetable treatment resistance in thyroid cancer by clonal hematopoiesis [CITE-Seq]

ABSTRACT: Anaplastic thyroid cancer (ATC) is a clinically aggressive malignancy associated with a dismal prognosis. Combined BRAF/MEK inhibition offers significant therapeutic benefit in patients with BRAFV600E-mutant ATCs. However, relapses are common and overall survival remains poor. Compared with differentiated thyroid cancer, a hallmark of ATCs is significant infiltration with myeloid cells, in particular macrophages. ATCs are most common in the aging population, which also has an increased incidence of clonal hematopoiesis (CH), including TET2 mutant CH. CH-mutant macrophages have been shown to accelerate CH-associated pathophysiology including atherosclerosis. However, the clinical and mechanistic contribution of CH-mutant clones to solid tumor biology, prognosis and therapeutic response has not been elucidated. Here we show that TET2-mutant CH is enriched in the tumor microenvironment of patients with solid tumors and that CH is associated with adverse prognosis in ATC patients. We find that Tet2-mutant macrophages selectively infiltrate mouse BrafV600E-mutant ATC and that their overexpression of Tgfβ-family ligands mediates resistance to BRAF/MEK inhibition. Importantly, inhibition of Tgfβ signaling restores sensitivity to MAPK pathway inhibition, opening a path for synergistic strategies to improve outcomes of patients with ATCs and concurrent CH.

ORGANISM(S): Mus musculus

PROVIDER: GSE275706 | GEO | 2026/09/28

REPOSITORIES: GEO