Targetable Treatment Resistance in Thyroid Cancer with Clonal Hematopoiesis

Tiedje, V.; Vela, P. S.; Yang, J. L.; Untch, B. R.; Boucai, L.; Stonestrom, A. J.; Costa, A. B.; Exposito, S. F.; Srivastava, A.; Kerpelev, M.; Greenberg, J.; Wereski, M.; Kulick, A.; Chen, K.; Qin, T.; Im, S.-Y.; Krishnan, A.; Benitez, A. R. M.; Pluvinet, R.; Sahin, M.; Menghrajani, K.; Krishnamoorthy, G. P.; De Stanchina, E.; Zehir, A.; Satija, R.; Knauf, J.; Bowman, R.; Esteller, M.; Devlin, S. M.; Berger, M.; Koche, R.; Fagin, J. A.; Levine, R.

doi:10.1101/2024.10.10.617685

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bioRxiv · 10.1101/2024.10.10.617685

Targetable Treatment Resistance in Thyroid Cancer with Clonal Hematopoiesis

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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 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, 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 BrafV600E-mutant ATC and that their overexpression of Tgf{beta}-family ligands mediates resistance to BRAF/MEK inhibition. Importantly, inhibition of Tgf{beta} signaling restores sensitivity to MAPK pathway inhibition, opening a path for synergistic strategies to improve outcomes of patients with ATCs and concurrent CH.

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Tiedje, V., Vela, P. S., Yang, J. L., Untch, B. R., Boucai, L., Stonestrom, A. J., Costa, A. B., Exposito, S. F., Srivastava, A., Kerpelev, M., Greenberg, J., Wereski, M., Kulick, A., Chen, K., Qin, T., Im, S.-Y., Krishnan, A., Benitez, A. R. M., Pluvinet, R., Sahin, M., Menghrajani, K., Krishnamoorthy, G. P., De Stanchina, E., Zehir, A., Satija, R., Knauf, J., Bowman, R., Esteller, M., Devlin, S. M., Berger, M., Koche, R., Fagin, J. A., Levine, R.. 2024-10-11. Targetable Treatment Resistance in Thyroid Cancer with Clonal Hematopoiesis. https://doi.org/10.1101/2024.10.10.617685

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