Dataset Information

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

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.

SUBMITTER: Chen CP

PROVIDER: S-EPMC10990975 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Chen Chiao-Ping CP Lin Shu-Fu SF Yeh Chun-Nan CN Huang Wen-Kuan WK Pan Yi-Ru YR Hsiao Yu-Tien YT Lo Chih-Hong CH Wu Chiao-En CE

Heliyon 20240330 7

<h4>Background</h4>Anaplastic thyroid cancer (ATC), a rare and aggressive malignancy with a poor prognosis, has shown promise with the approved dabrafenib/trametinib combination for BRAF<sup>V600E</sup> mutation. Co-occurring PI3KCA mutations, identified as negative prognostic factors in lung cancer with BRAF<sup>V600E</sup> mutation, emphasize the need to target both pathways. Exploring trametinib and alpelisib combination becomes crucial for ATC.<h4>Methods</h4>A patient-derived xenograft (PDX ...[more]

PMID: 38576565

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Project description:BackgroundCombined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up.Patients and methodsROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.ResultsAt data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib.ConclusionsThese updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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