A preclinical evaluation of the PI3K alpha/delta dominant inhibitor BAY 80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2-targeted therapies trastuzumab and lapatinib

Abstract Background Targeted therapies have been hypothesized to prolong survival in the management of patients with intracranial metastatic disease (IMD), but, paradoxically, to increase IMD incidence by improving systemic disease control and prolonging survival from the primary tumor. The real-world benefits of targeted therapy in management of patients with IMD are unclear, as clinical trials have excluded patients with IMD and lacked endpoints reporting intracranial outcomes. Methods This retrospective cohort study included all patients in Ontario, Canada, diagnosed with IMD from 2005 to 2018 with primary diagnoses of breast cancer, lung or bronchus cancer, or melanoma, and control patients matched by primary disease without IMD. Kaplan-Meier and multivariable Cox regression analyses were performed to compare overall survival (OS) between patient sub-cohorts divided by primary disease and stratified by targeted therapy receipt or IMD status. Results Post-IMD targeted therapy was associated with prolonged OS in patients with HER2-positive breast cancer (HR 0.41; 95% CI, 0.33–0.5), EGFR-positive lung cancer (HR 0.28; 95% CI, 0.23–0.34), and BRAF-positive melanoma (HR 0.2; 95% CI, 0.14–0.29), compared to those who did not receive post-IMD targeted therapy. Presence of IMD was associated with shorter OS in patients with metastatic HER2-positive breast cancer (HR 1.8; 95% CI, 1.56–2.08) and metastatic EGFR-positive lung cancer (HR 1.22; 95% CI, 1.08–1.39) but not metastatic BRAF-positive melanoma (HR 1.11; 95% CI, 0.77–1.61), compared to those without IMD. Conclusions Our findings show that real-world use of targeted therapies was associated with prolonged OS in patients with IMD in the setting of HER2-positive breast cancer, EGFR-positive lung cancer, and BRAF-positive melanoma. Inclusion of patients with IMD in clinical trials and use of endpoints that interrogate IMD will be critical to determine the role of targeted therapies in the management of patients with IMD.

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Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1815034116 ◽

2019 ◽

Vol 116 (9) ◽

pp. 3863-3872 ◽

Cited By ~ 17

Author(s):

Sandra Blasco-Benito ◽

Estefanía Moreno ◽

Marta Seijo-Vila ◽

Isabel Tundidor ◽

Clara Andradas ◽

...

Keyword(s):

Breast Cancer ◽

Cannabinoid Receptor ◽

Acquired Resistance ◽

Diagnostic Tools ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted. Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CB2R. We show that HER2 physically interacts with CB2R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis. The cannabinoid Δ9-tetrahydrocannabinol (THC) disrupts HER2–CB2R complexes by selectively binding to CB2R, which leads to (i) the inactivation of HER2 through disruption of HER2–HER2 homodimers, and (ii) the subsequent degradation of HER2 by the proteasome via the E3 ligase c-CBL. This in turn triggers antitumor responses in vitro and in vivo. Selective targeting of CB2R transmembrane region 5 mimicked THC effects. Together, these findings define HER2–CB2R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.

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