EGFR/Notch Antagonists Enhance the Response to Inhibitors of the PI3K-Akt Pathway by Decreasing Tumour-Initiating Cell Frequency

Purpose: Both EGFR and PI3K-Akt signalling pathway have been used as therapeutically actionable targets, but resistance is frequently reported. In this report, we show that enrichment of the cancer stem cell (CSC) subsets and dysregulation of Notch signalling underlie the challenges to therapy and describe the development of bispecific antibodies targeting both HER and Notch signalling. Experimental Design: We utilized cell-based models to study Notch signalling in drug induced CSC expansion. Both cancer cell line models and patient-derived xenograft tumours were used to evaluate the antitumour effects of bispecific antibodies. Cell assays, flow cytometry, qPCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts. Results: We found that EGFR/Notch targeting bispecific antibodies exhibited a notable anti-stem cell effect in both in vitro and in vivo assays. Bispecific antibodies delayed the occurrence of acquired resistance to EGFR inhibitors in TNBC cell-line based models and showed efficacy in patient-derived xenografts. Moreover, the EGFR/Notch bispecific antibody PTG12 in combination with GDC-0941 exerted a stronger antitumour effect than the combined therapy of PI3K inhibitor with EGFR inhibitors or tarextumab in a broad spectrum of epithelial tumours. Mechanistically, bispecific antibody treatment inhibits the stem cell-like subpopulation, reduces tumour-initiating cell frequency and downregulates the mesenchymal gene expression. Conclusions: These findings suggest that the co-blockade of EGFR and Notch signalling has the potential to increase the response to PI3K inhibition and PTG12 may gain clinical efficacy when combined with PI3K blockage in cancer treatment.

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