Targetable treatment resistance in thyroid cancer with clonal hematopoiesis
Abstract:
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.
Insights
Clonal hematopoiesis with TET2 mutations in macrophages promotes anaplastic thyroid cancer (ATC) growth and BRAF/MEK inhibitor resistance. Targeting TGFβ signaling may overcome this resistance, improving outcomes for patients with ATC and concurrent CH.
Area of Science:
- Oncology
- Cancer Biology
- Hematology
Background:
- Anaplastic thyroid cancer (ATC) is aggressive with poor prognosis, despite BRAF/MEK inhibition for BRAF V600E mutations.
- ATC features significant myeloid cell infiltration, particularly macrophages, and is common in aging populations with TET2-mutant clonal hematopoiesis (CH).
- The role of CH-mutant clones in solid tumors, including their impact on prognosis and treatment response, is largely unknown.
Purpose of the Study:
- To investigate the role of TET2-mutant clonal hematopoiesis (CH) in the tumor microenvironment of anaplastic thyroid cancer (ATC).
- To determine if CH-mutant macrophages contribute to ATC progression and resistance to BRAF/MEK inhibition.
- To explore therapeutic strategies combining MAPK pathway inhibition with TGFβ signaling blockade.
Main Methods:
- Analysis of TET2-mutant CH enrichment in solid tumor microenvironments and ATC patient prognosis.
- Infiltration of Tet2-mutant macrophages into mouse Braf V600E-mutant ATC models.
- Assessment of TGFβ-family ligand overexpression by mutant macrophages and its role in BRAF/MEK inhibitor resistance.
- Evaluation of TGFβ signaling inhibition in restoring sensitivity to MAPK pathway inhibitors.
Main Results:
- TET2-mutant CH is enriched in solid tumor microenvironments and linked to worse prognosis in ATC patients.
- Tet2-mutant macrophages selectively infiltrate Braf V600E-mutant ATC in mice.
- Overexpression of TGFβ-family ligands by these macrophages mediates resistance to BRAF/MEK inhibition.
- Inhibiting TGFβ signaling restores sensitivity to MAPK pathway inhibitors in preclinical models.
Conclusions:
- TET2-mutant CH in macrophages represents a mechanism of resistance to BRAF/MEK inhibitors in anaplastic thyroid cancer.
- Targeting TGFβ signaling offers a potential synergistic strategy to improve treatment outcomes for ATC patients with concurrent CH.
- This study highlights the importance of considering clonal hematopoiesis in the tumor microenvironment for cancer therapy.
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