HER3 Limits the Antitumor Activity of PI3K–AKT Inhibitors in TNBC

Overexpression of the EGF receptor (EGFR) and hyperactivation of the phosphoinositide 3-kinase (PI3K) pathway occur in a large fraction of triple-negative breast cancers (TNBC). However, EGFR or PI3K inhibitors have not led to durable responses in TNBC, possibly due to compensatory activation of other receptor tyrosine kinases. Tao and colleagues found that the PI3K inhibitor GDC-0941 and the AKT inhibitor GDC-0068 each increased human EGF receptor 3 (HER3) abundance and induced HER3 and EGFR phosphorylation in EGFR-positive, PTEN-null TNBC cell lines. Combining MEHD7945A, an antibody that targets both EGFR and HER3, with either GDC-0941 or GDC-0068 impeded ligand-induced EGFR and HER3 activation and significantly impaired TNBC cell proliferation when compared with PI3K–AKT inhibition alone. Consistent with this finding, combined MEHD7945A and either GDC-0941 or GDC-0068 treatment markedly impaired tumor growth of TNBC patient-derived xenografts compared with monotherapy and prevented HER3 and EGFR activation in tumor xenograft samples. Moreover, pharmacologic or genetic inhibition of HER3 was significantly more effective than the anti-EGFR antibody cetuximab in sensitizing TNBC cells to PI3K–AKT inhibitors in vitro, and combined cetuximab and GDC-0941 or GDC-0068 treatment did not significantly enhance tumor xenograft growth inhibition compared with single-agent treatment, suggesting that HER3 activation limits the efficacy of PI3K pathway inhibitors in TNBC. Notably, high pretreatment EGFR expression was associated with an increased probability of achieving pathologic complete response (pCR) following combination anti-EGFR and chemotherapy treatment in patients with TNBC, and of those patients that did not achieve pCR, a statistically significant increase in HER3 expression and HER3–EGFR heterodimerization was observed in the majority of residual tumors examined. Together, these findings implicate HER3 as a compensatory mechanism to PI3K–AKT inhibition and provide a rationale for clinical evaluation of combined EGFR, HER3, and PI3K–AKT inhibition in patients with EGFR-positive TNBC.

Tao JJ, Castel P, Radosevic-Robin N, Elkabets M, Auricchio N, Aceto N, et al. Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. Sci Signal 2014;7:ra29.

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