Synergistic effects of the combination of trametinib and alpelisib in anaplastic thyroid cancer with BRAF and PI3KCA co-mutations

Chiao-Ping Chen; Shu-Fu Lin; Chun-Nan Yeh; Wen-Kuan Huang; Yi-Ru Pan; Yu-Tien Hsiao; Chih-Hong Lo; Chiao-En Wu

doi:10.1016/j.heliyon.2024.e29055

Synergistic effects of the combination of trametinib and alpelisib in anaplastic thyroid cancer with BRAF and PI3KCA co-mutations

Heliyon. 2024 Mar 30;10(7):e29055. doi: 10.1016/j.heliyon.2024.e29055. eCollection 2024 Apr 15.

Authors

Chiao-Ping Chen^{1

2}, Shu-Fu Lin³, Chun-Nan Yeh^{2

4}, Wen-Kuan Huang^{1

2}, Yi-Ru Pan^{2

4}, Yu-Tien Hsiao^{1

2}, Chih-Hong Lo^{1

2}, Chiao-En Wu^{1

2}

Affiliations

¹ Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
² Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
³ Division of Endocrinology and Metabolism, Department of Internal Medicine, New Taipei Municipal TuCheng Hospital (Built and Operated by Chang Gung Medical Foundation), College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁴ Department of General Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

Abstract

Background: Anaplastic thyroid cancer (ATC), a rare and aggressive malignancy with a poor prognosis, has shown promise with the approved dabrafenib/trametinib combination for BRAF^V600E mutation. Co-occurring PI3KCA mutations, identified as negative prognostic factors in lung cancer with BRAF^V600E mutation, emphasize the need to target both pathways. Exploring trametinib and alpelisib combination becomes crucial for ATC.

Methods: A patient-derived xenograft (PDX) and primary cell line were obtained from an ATC patient with BRAF and PI3KCA co-mutation. Individual testing of targeted therapies against BRAF, MEK, and PI3KCA was followed by a combination treatment. Synergistic effects were evaluated using the combination index. Immunoblotting assessed the efficacy, with validation performed using a PDX model.

Results: In this study, the ATC0802 cell line and PDX were established from a refractory ATC patient. NGS revealed BRAF and PI3KCA co-mutations pre- and post-dabrafenib/trametinib treatment. Trametinib/alpelisib combination showed synergy, suppressing both pERK and pAKT levels, unlike monotherapies or BRAF knockdown. The combination induced apoptosis and, in the PDX model, demonstrated superior tumor growth inhibition compared to monotherapies.

Conclusions: The combination of trametinib and alpelisib showed promise as a strategy for treating ATC with co-mutations in BRAF and PI3KCA, both in vitro and in vivo. This combination offers insights into overcoming resistance to BRAF-targeted treatments in ATC with mutations in BRAF and PI3KCA.

Keywords: Alpelisib; Anaplastic thyroid cancer; BRAF; Dabrafetnib; PI3KCA; Trametinib.