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The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer
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The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer
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The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer
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Journal Article
The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer
2025
Overview
Loss of PTEN expression, via homozygous or hemizygous deletion, is common in
PIK3CA
mutant ER + BC tumors. We assessed reduction of PTEN protein expression on AKT inhibitor capivasertib efficacy in
PIK3CA
altered tumors. In
PIK3CA
altered, PTEN protein high models, PI3Kα and AKT inhibition was effective, however ablation and partial PTEN expression reduction attenuated PI3Kαi but not AKTi efficacy, alone or combined with fulvestrant. Efficacy was FOXO3 dependent and associated with FOXM1 downregulation. FOXO3A deletion reduced response to capivasertib, and increased FOXM1 expression. Long term capivasertib exposure of ER+ BC cells upregulated FOXM1 expression. Downregulating FOXM1 expression reversed resistance to capivasertib, while FOXM1 overexpression reduced capivasertib efficacy. Collectively this suggests the AKT-FOXO3-FOXM1 axis plays a pivotal role in response to AKTi in ER+ breast cancer with
PIK3CA
mutations with and without expression of PTEN, that FOXO3 expression loss can mediate resistance, and that FOXM1 downregulation is a potential biomarker of response.
