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Ref Type Journal Article
PMID (37713162)
Authors Rose MM, Nassar KW, Sharma V, Schweppe RE
Title AKT-independent signaling in PIK3CA-mutant thyroid cancer mediates resistance to dual SRC and MEK1/2 inhibition.
Journal Vol Issue Date Pages Journal Short Title
Medical oncology (Northwood, London, England) 40 10 2023 Sep 15 299 Med Oncol
URL
Abstract Text Anaplastic thyroid cancer (ATC) is a rare and aggressive disease with 90% of patients succumbing to this disease 1 year after diagnosis. The approval of the combination therapy of a BRAF inhibitor dabrafenib with the MEK1/2 inhibitor trametinib has improved the overall survival of ATC patients. However, resistance to therapy remains a major problem. We have previously demonstrated combined inhibition of Src with dasatinib and MEK1/2 with trametinib synergistically inhibits growth and induces apoptosis in BRAF- and RAS-mutant thyroid cancer cells, however PIK3CA-mutant cells exhibit a mixed response. Herein, we determined that AKT is not a major mediator of sensitivity and instead PIK3CA-mutants that are resistant to combined dasatinib and trametinib have sustained activation of PDK1 signaling. Furthermore, combined inhibition of PDK1 and MEK1/2 was sufficient to reduce cell viability. These data indicate PDK1 inhibition is a therapeutic option for PIK3CA mutations that do not respond to combined Src and MEK1/2 inhibition.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PIK3CA W11C missense unknown PIK3CA W11C does not lie within any known functional domains of the Pik3ca protein (UniProt.org). W11C has been identified in the scientific literature (PMID: 33754015, PMID: 37713162), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Jan 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E PIK3CA N1044S thyroid gland anaplastic carcinoma resistant Dasatinib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, an anaplastic thyroid cancer cell line harboring BRAF V600E and PIK3CA N1044S was resistant to the combination of Sprycel (dasatinib) and Mekinist (trametinib) in culture (PMID: 37713162). 37713162
BRAF V600E PIK3CA W11C PIK3CA E542K thyroid gland papillary carcinoma sensitive Dasatinib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Sprycel (dasatinib) and Mekinist (trametinib) inhibited viability of a papillary thyroid cancer cell line harboring BRAF V600E and PIK3CA E542K and W11C in culture (PMID: 37713162). 37713162
BRAF V600E PIK3CA M1043I thyroid gland anaplastic carcinoma sensitive Dasatinib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Sprycel (dasatinib) and Mekinist (trametinib) inhibited viability of an anaplastic thyroid cancer cell line harboring BRAF V600E and PIK3CA M1043I in culture (PMID: 37713162). 37713162
BRAF V600E PIK3CA E542K thyroid gland anaplastic carcinoma sensitive GSK2334470 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of GSK2334470 sensitized an anaplastic thyroid cancer cell line harboring BRAF V600E and PIK3CA E542K to Mekinist (trametinib) treatment as demonstrated by a reduction in viability in culture (PMID: 37713162). 37713162
BRAF V600E PIK3CA N1044S thyroid gland anaplastic carcinoma resistant Dasatinib + MK2206 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of MK2206 did not sensitize an anaplastic thyroid cancer cell line harboring BRAF V600E and PIK3CA N1044S to Sprycel (dasatinib) and Mekinist (trametinib) combination treatment in culture (PMID: 37713162). 37713162
BRAF V600E PIK3CA E542K thyroid gland anaplastic carcinoma resistant Dasatinib + MK2206 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of MK2206 did not sensitize an anaplastic thyroid cancer cell line harboring BRAF V600E and PIK3CA E542k to Sprycel (dasatinib) and Mekinist (trametinib) combination treatment in culture (PMID: 37713162). 37713162
BRAF V600E PIK3CA H1047R thyroid gland anaplastic carcinoma sensitive Dasatinib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Sprycel (dasatinib) and Mekinist (trametinib) inhibited viability of an anaplastic thyroid cancer cell line harboring BRAF V600E and PIK3CA H1047R in culture (PMID: 37713162). 37713162
BRAF V600E PIK3CA E542K thyroid gland anaplastic carcinoma resistant Dasatinib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, an anaplastic thyroid cancer cell line harboring BRAF V600E and PIK3CA E542K was resistant to the combination of Sprycel (dasatinib) and Mekinist (trametinib) in culture (PMID: 37713162). 37713162
BRAF V600E PIK3CA N1044S thyroid gland anaplastic carcinoma sensitive GSK2334470 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of GSK2334470 sensitized an anaplastic thyroid cancer cell line harboring BRAF V600E and PIK3CA N1044S to Mekinist (trametinib) treatment as demonstrated by a reduction in viability in culture (PMID: 37713162). 37713162