A novel oncogenic BTK isoform is overexpressed in colon cancers and required for RAS-mediated transformation

Bruton’s tyrosine kinase (BTK) is essential for B-cell proliferation/differentiation and it is generally believed that its expression and function are limited to bone marrow-derived cells. Here, we report the identification and characterization of p65BTK, a novel isoform abundantly expressed in colon carcinoma cell lines and tumor tissue samples. p65BTK protein is expressed, through hnRNPK-dependent and IRES-driven translation, from a transcript containing an alternative first exon in the 5’UTR, and is post-transcriptionally regulated, via hnRNPK, by the MAPK pathway. p65BTK is endowed with strong transforming activity that depends on active ERK1/2 and its inhibition abolishes RAS transforming activity. Accordingly, p65BTK overexpression in colon cancer tissues correlates with ERK1/2 activation. Moreover, p65BTK inhibition affects growth and survival of colon cancer cells. Our data reveal that BTK, via p65BTK expression, is a novel and powerful oncogene acting downstream of the RAS/MAPK pathway and suggest that its targeting may be a promising therapeutic approach