The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation

Abstract

Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these micro-environments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases.

A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance

“…Addition of the HER3 ectodomain at increasing concentrations triggered a rapid and reversible surge in binding (response units), indicating a specific interaction between SorLA and HER3 ectodomains ( Figure 4D). The strength of this interaction decreased with increasing pH ( Figure 4D-F), indicating that this interaction is pH-sensitive, similar to the interaction of SorLA with the amyloid precursor protein (Mehmedbasic et al, 2015). A similar interaction pattern was observed when increasing concentrations of the HER2 ectodomain were applied at different pH values ( Figure S4A-C).…”

“…To determine whether SorLA interacts directly with the extracellular domains of HER2 and HER3, we performed surface plasmon resonance (SPR) analysis, an assay that records protein interaction with an immobilized target on a microchip (Schuck, 1997). SPR analyses were performed using immobilized SorLA ectodomain under pH conditions corresponding to either endosomal (pH 5 & 6) or cell-surface compartments (7.4) (Maxfield and McGraw, 2004;. Addition of the HER3 ectodomain at increasing concentrations triggered a rapid and reversible surge in binding (response units), indicating a specific interaction between SorLA and HER3 ectodomains ( Figure 4D).…”

Consensus guidelines for the use and interpretation of angiogenesis assays

“…For example, it is possible to quantify the abnormalities in structure and function that are hallmarks of tumor angiogenesis, and then assess how these abnormalities change when the vasculature is normalized with anti-angiogenic or anti-fibrotic therapies [478, 500, 508–513]. Intravital optical microscopy [514] has also been useful for calibrating clinical imaging modalities in patients [515].…”

A network modeling approach to elucidate drug resistance mechanisms and predict combinatorial drug treatments in breast cancer

“…As a result of the development of PI3K inhibitors, there has been an increased interest in investigating the resistance mechanisms to PI3K inhibitors in the context of breast cancer, and several studies have been done in this direction (41)(42)(43)(44)(45)(46)(47)(48)(49). These studies have elucidated several resistance mechanisms to PI3KCA inhibitors such as PIK3CB signaling (an alternative PI3K isoform), HER3 (ERBB3) receptor activity (which is upstream of PI3K, and strongly activates the MAPK and PI3K pathway), mTORC1 signaling (which would otherwise be activated by the PI3K pathway), estrogen receptor (ER) transcriptional regulatory activity (which provides PI3K-independent means of promoting proliferation), , and signaling through the PIM (PIM1, PIM2, and PIM3), SGK (SGK1, SGK2, and SGK3), and PDK1 protein kinases (which act independently of PI3K, and have functions similar to AKT).…”