Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer
Introduction
Inhibition of phosphatidylinositol-3-kinase (PI3K) promotes apoptosis when combined with estrogen deprivation in estrogen receptor (ER)-positive breast cancer. This study aimed to: (1) identify effective combinations of PI3K pathway inhibitors with endocrine therapies, (2) evaluate the influence of PI3K pathway mutations and estrogen dependency on treatment response, and (3) determine the role of *PIK3CA* mutations in recurrent disease.
Methods
The PI3K catalytic subunit inhibitor BKM120, the NVP-BGT226 mammalian target of rapamycin (mTOR) inhibitor RAD001, and the dual PI3K/mTOR inhibitor BGT226 were tested on ER-positive breast cancer cell lines both before and after long-term estrogen deprivation (LTED). The effects of estradiol deprivation and the ER downregulator fulvestrant on PI3K inhibitor-induced apoptosis were also analyzed. *PIK3CA* hotspot mutations were assessed in 51 recurrent or metastatic breast cancers and correlated with ER status and survival outcomes.
Results
Apoptosis was most pronounced in short-term estrogen-deprived cells with *PIK3CA* mutations and loss of phosphatase and tensin homolog (PTEN). The strongest apoptotic response was observed with BGT226, followed by BKM120, and then RAD001. Estradiol blocked PI3K inhibitor-induced apoptosis under short-term estrogen deprivation, underscoring the importance of estrogen-deprivation therapy in enhancing PI3K inhibitor efficacy in frontline settings. MCF7 LTED cells showed resistance to PI3K inhibitors, which was reversed by fulvestrant. In contrast, T47D LTED cells lost ER expression and remained sensitive to PI3K inhibitors independently of ER status. *PIK3CA* mutations were detected in 48% of relapsed ER-positive cases and were associated with persistent ER expression and late disease recurrence.
Conclusions
Estrogen deprivation enhanced the apoptotic effects of PI3K and dual PI3K/mTOR inhibitors in ER-positive breast cancer, supporting the use of PI3K inhibitors in combination with aromatase inhibitors as a first-line treatment strategy. In LTED models, the response to PI3K inhibitors was influenced by ER expression: when ER expression persisted, fulvestrant augmented the apoptotic response; when ER was lost, PI3K inhibitor monotherapy was sufficient. Although *PIK3CA* mutations were associated with late recurrences, these mutations were prevalent in metastatic disease and often accompanied by persistent ER expression. Thus, targeting *PIK3CA*-mutant tumors with a PI3K pathway inhibitor and fulvestrant offers a promising approach for managing aromatase-inhibitor-resistant ER-positive relapsed breast cancer.