Characterization of a novel isoform of Bruton's Tyrosine Kinase (BTK) involved in resistance to drug-induced apoptosis of carcinoma cells

Cancer is a multistep process in which mutation of 4 to 6 genes has to occur for the cell to become fully oncogenic. Very often, genes affected by such mutations encode for molecules belonging to the pathways allowing DNA repair or controlling the apoptotic process. Many anticancer drugs act by inducing DNA damage, which in turn triggers apoptosis. Inability of tumour cells to undergo chemotherapy-induced apoptosis is a main mechanism of drug resistance. Therefore, in order to find rational targets to tailor therapy is necessary to identify novel genes involved in modulating apoptosis induced by chemotherapeutics. Recently in our lab a loss-of-function RNAi-library-based phenotypic screen has been performed which identified 49 novel genes whose silencing reverts 5-fluoraouracil (FU) resistance in a model colon cancer cell line (HCT116p5KO). The aim of the project was to study the role of one of the targets identified in the abovementioned screen, the Bruton’s tyrosine kinase (BTK), so far assumed to be expressed only in hematopoietic lineages. Our findings suggest that BTK could be an interesting candidate to be targeted in the therapy of drug-resistant colon cancers and a marker of drug-resistance.