Targetable treatment resistance in thyroid cancer with clonal hematopoiesis

Anaplastic thyroid cancer (ATC) is a clinically aggressive malignancy with a dismal prognosis.

Combined BRAF/MEK inhibition offers significant therapeutic benefit in patients with BRAF (V600E) -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, particularly macrophages.

ATCs are most common in the aging population, which also has an increased incidence of TET2 -mutant clonal hematopoiesis (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 tumour biology, prognosis and therapeutic response has not been elucidated.

Here we show that TET2 -mutant CH is enriched in the tumour microenvironment of patients with solid tumours and associated with adverse prognosis in ATC patients.

We find that Tet2 -mutant macrophages selectively infiltrate mouse Braf (V600E) -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.