Inhibiting endocytosis to enhance cetuximab, trastuzumab and Bavencio antitumor efficacy

INDICATION: Breast cancer; colorectal cancer; skin cancer

Blocking endocytosis with DMN inhibitors could enhance the efficacy of cetuximab, trastuzumab and Bavencio avelumab against skin, breast and colorectal cancers. The mAbs target EGFR, HER2 and PD-L1, respectively. In human squamous cell carcinoma cell (SCC) lines, a dynamin inhibitor tool compound increased cetuximab target-binding and subsequent tumor cell death. Combination of the dynamin inhibitor tool compound with trastuzumab led to similar effects in human breast cancer cell lines. In a xenograft mouse model of cetuximab-resistant SCC, the dynamin inhibitor prochlorperazine plus cetuximab reduced tumor volume and prevented lung metastases. In a syngeneic mouse model of colorectal cancer, prochlorperazine plus Bavencio reduced tumor volume and increased survival compared with either drug alone. The safety dose-escalation Phase Ib CESTEM-I trial of prochlorperazine plus cetuximab for metastatic head and neck SCC and triple-negative breast cancer (TNBC) has been completed; next steps include a Phase II trial. ...