Abstract SP139: HER2 targeted therapy: Determinants of response and mechanisms of resistance
Authors: Schiff R , Veeraraghavan J , De Angelis C , Osborne C , Rimawi MF 
Published: February 2021

Abstract
HER2-positive (+) breast cancer (BC), accounting for 15-20% of all BCs, is characterized by overexpression, mostly via gene amplification, of HER2. HER2 is a key member of the HER family of 4 tyrosine kinase receptors. Multiple clinically available HER2-targeted therapies, including monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates have revolutionized the outcome of patients with HER2+ BC. Despite these effective therapies, intrinsic and acquired resistance still occurs, posing a major challenge in the clinical management of this disease. A better understanding of the determinants of response and mechanisms of resistance may help develop personalized treatment approaches and new strategies to overcome resistance. Tumors that are truly addicted to HER2, clinically reflected especially under chemotherapy-sparing HER2-targeted therapy regimens, are associated with high and homogeneous levels of HER2 gene amplification, protein, and activity. Even in these HER2-addicted tumors, the efficacy of anti-HER2 therapy can be jeopardized by deregulations in the downstream PI3K pathway (e.g., PIK3CA mutations), which can lead to constitutive activation of the PI3K/AKT pathway and resistance. Given the functional redundancy of signaling from multiple HER receptor dimers and compensatory signaling within the pathway, dual anti-HER2 therapy has proven superior to single agents in achieving a more comprehensive blockade of the entire HER receptor layer and in anti-tumor efficacy. Further, in the HER2+ tumors that co-express ER, an unblocked, re-expressed and/or reactivated ER signaling can provide alternative proliferative and survival signals to evade sustained HER2 blockade, thus underscoring the need for concurrent blockade of HER2 and ER signaling. Nevertheless, effective inhibition of HER2 might prove challenging in some cases due to molecular masking of the HER receptors (e.g., mucins) or due to the de novo presence or acquisition of genetic, epigenetic or post-translational alterations in HER2 itself, including activating HER2 mutations (e.g., L755S), and p95HER2. We recently reported that acquired resistance to HER2-targeted therapy, especially TKIs, is mediated by the common HER2 L755S mutation, the clinical importance of which is underscored by the observation that this and other HER mutations are further enriched in the metastatic lesions compared to primary HER2+ tumors. On the other hand, when HER2 does remain effectively inhibited under potent HER2-targeted therapy, resistance can arise due to the upregulation of alternative escape pathways that transmit proliferative stimuli. These include activation of other receptor tyrosine kinases (e.g., AXL, FGFR), other downstream/intracellular signaling (e.g., SRC, YES1), or metabolic pathways (e.g., FASN and mevalonate pathways). Our recent data suggest that the mevalonate pathway offers an escape mechanism by providing alternative signaling through the YAP/TAZ-mTORC1-survivin axis to activate a transcriptional program that promotes resistant cell proliferation and survival, which can be overcome using inhibitors of mevalonate pathway (e.g., statins). Importantly, activation of the key cell cycle regulator cyclin D1/CDK4 complex has been shown to mediate resistance to HER2-targeted therapy and that CDK4/6 inhibitors, at least partly by also inhibiting mTORC1 activity, can overcome this resistance. Finally, the role of tumor microenvironment, including host immune components (e.g., TILs) and extracellular matrix components signaling via integrins, have been shown to play a role in modulating tumor response to treatment and in resistance. Together, these findings suggest new strategies to enhance sensitivity and overcome resistance to HER2-targeted therapy, some of which are already under clinical development.
Citation Format: R Schiff, J Veeraraghavan, C De Angelis, C Osborne, MF Rimawi. HER2 targeted therapy: Determinants of response and mechanisms of resistance [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP139.