Reference Detail

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 H1047R	anaplastic thyroid 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 N1044S	anaplastic thyroid 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
BRAF V600E PIK3CA E542K	anaplastic thyroid 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	anaplastic thyroid 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 M1043I	anaplastic thyroid 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 W11C PIK3CA E542K	papillary thyroid 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 E542K	anaplastic thyroid 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 E542K	anaplastic thyroid 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 N1044S	anaplastic thyroid 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