IKZF2-ERBB4 gene fusion leads toERBB4overexpression in Anal Squamous Cell Carcinoma but with no benefit for ERBB4 inhibition

Abstract

Anal squamous cell carcinoma (ASCC) is a rare tumour, but with increasing incidence for local and metastatic tumours. Current therapy is based on chemoradiotherapy, associated with immunotherapy in advanced stages, with frequent side effects, poor results in advanced stages and recurrence. New therapeutics, including targeted therapies, are then needed. In this context, we identified here a IKZF2-ERBB4 gene fusion in a patient ASCC tumour, leading to overexpressed mRNA encoding a functional ERBB4 protein. This gene fusion has been already reported in other tumour types but not yet investigated as therapeutical target. The matched patient tumour-derived xenograft displays the same gene fusion and mRNA overexpression. It provided biological material for anti-ERBB4 testing in different cell models (in vivo xenograft, in vitro cell cultures). We used afatinib and lapatinib, 2 chemical pan-ERBB inhibitors approved in clinics, with anti-ERBB4 properties. ERBB4 inhibition did not lead to tumour growth inhibition although afatinib and lapatinib dramatically decreased ERBB4 phosphorylation with impact on downstream signalling MAPK/ERK but not PI3K/AKT pathways. Likewise, specific ERBB4 knock-outing did not affect tumour cell proliferation. These "negative" results must be put in line with reported potential crosstalk between PI3K/AKT and MAPK/ERK pathways in therapeutic resistance.