Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer

Abstract

Although antiestrogen therapies targeting estrogen receptor (ER) α signaling prevent disease recurrence in the majority of patients with hormone-dependent breast cancer, a significant fraction of patients exhibit de novo or acquired resistance. Currently, the only accepted mechanism linked with endocrine resistance is amplification or overexpression of the ERBB2 (human epidermal growth factor receptor 2 [HER2]) proto-oncogene. Experimental and clinical evidence suggests that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway, the most frequently mutated pathway in breast cancer, promotes antiestrogen resistance. PI3K is a major signaling hub downstream of HER2 and other receptor tyrosine kinases. PI3K activates several molecules involved in cell-cycle progression and survival, and in ER-positive breast cancer cells, it promotes estrogen-dependent and -independent ER transcriptional activity. Preclinical tumor models of antiestrogen-resistant breast cancer often remain sensitive to estrogens and PI3K inhibition, suggesting that simultaneous targeting of the PI3K and ER pathways may be most effective. Herein, we review alterations in the PI3K pathway associated with resistance to endocrine therapy, the state of clinical development of PI3K inhibitors, and strategies for the clinical investigation of such drugs in hormone receptor-positive breast cancer.

Fig 1.

Reciprocal crosstalk between estrogen receptor (ER) α and growth factor receptor signaling pathways. Receptor tyrosine kinases (RTKs) and G-protein–coupled receptors activate phosphatidylinositol 3-kinase (PI3K; blue) and MEK signaling pathways. These signal transducers can then phosphorylate ER (green) and/or coactivators and corepressors to modulate ER transcriptional activity not necessarily dependent on ER ligands. In turn, ER transcribes genes encoding components of growth factor signaling pathways, thus completing signaling cycle of RTKs to ER to RTKs. ER also complexes with RTKs and Src to rapidly induce nongenomic signaling. ER-interacting proteins shown in color. EGFR, epidermal growth factor receptor; IGF-1R, insulin-like growth factor-1 receptor; IGFBP, insulin-like growth factor binding protein; IRS-1, insulin receptor substrate 1; JNK, c-Jun N-terminal kinase; PTEN, phosphatase and tensin homolog; SGK3, serum/glucocorticoid-regulated kinase 3; TGFα, transforming growth factor alpha; TORC1, target of rapamycin complex 1.

Fig 2.

Diagram of neoadjuvant clinical trial with phosphatidylinositol 3-kinase (PI3K) pathway inhibitor. Patients with estrogen receptor (ER) –positive breast cancer eligible for neoadjuvant therapy randomly assigned to standard treatment (eg, aromatase inhibitor [AI]) with or without PI3K pathway inhibitor. Core biopsies obtained before and after 2 weeks of therapy to document effects on tumor cell proliferation, apoptosis, and pathway inactivation (ie, downregulation of P-AKT, P-S6, P–proline-rich AKT substrate 40 by immunohistochemistry). Incorporation of noninvasive [¹⁸F]fluorodeoxyglucose (FDG) –positron emission tomography (PET) at 2 weeks could identify early metabolic changes; however, PI3K pathway inhibitors may induce hyperglycemia,^– which could limit utility of FDG-PET. Primary end point of clinical response could be evaluated after approximately 4 to 6 months of therapy by measuring tumor with calipers, ultrasound (U/S), and/or mammography. Absence of tumor in surgical specimen would be scored as pathologic complete response (CR). Rate of breast-conserving surgery could be compared between both arms. Molecular mining of baseline, 2-week, and surgical biopsies could identify biomarkers that could be used for selection of patients enrolled onto subsequent studies of combination. HER2, human epidermal growth factor receptor 2; TUNEL, terminal deoxynucleotidyl nick-end labeling.