BTK inhibitors synergise with 5‐FU to treat drug‐resistant TP53‐null colon cancers

Abstract

Colorectal cancer (CRC) is the fourth cause of death from cancer worldwide mainly due to the high incidence of drug-resistance. During a screen for new actionable targets in drug-resistant tumours we recently identified p65BTK-a novel oncogenic isoform of Bruton's tyrosine kinase. Studying three different cohorts of patients here we show that p65BTK expression correlates with histotype and cancer progression. Using drug-resistant TP53-null colon cancer cells as a model we demonstrated that p65BTK silencing or chemical inhibition overcame the 5-fluorouracil resistance of CRC cell lines and patient-derived organoids and significantly reduced the growth of xenografted tumours. Mechanistically, we show that blocking p65BTK in drug-resistant cells abolished a 5-FU-elicited TGFB1 protective response and triggered E2F-dependent apoptosis. Taken together, our data demonstrated that targeting p65BTK restores the apoptotic response to chemotherapy of drug-resistant CRCs and gives a proof-of-concept for suggesting the use of BTK inhibitors in combination with 5-FU as a novel therapeutic approach in CRC patients.

Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway

“…Apoptosis promotion has been shown to be a crucial mechanism in CRC treatment. 28 Relative expression ratio of Bcl-2 and Bax has been reported as an important factor in determining the fate of tumor cells to undergo apoptosis, while cleaved-caspase-3 is shown as an indispensable terminal shear enzyme in apoptosis. 29 Our data revealed that DHM can significantly activate the intrinsic apoptotic pathway in CRC cells in a dose-dependent manner; however, not in normal human colonic mucosal epithelial cells (NCM460).…”

“…This suggested that DHM might be attenuating CRC cell invasion by reducing MMP2‐ and MMP9‐mediated injury to the components of extracellular matrix. Apoptosis promotion has been shown to be a crucial mechanism in CRC treatment 28 . Relative expression ratio of Bcl‐2 and Bax has been reported as an important factor in determining the fate of tumor cells to undergo apoptosis, while cleaved‐caspase‐3 is shown as an indispensable terminal shear enzyme in apoptosis 29 .…”

Important players in carcinogenesis as potential targets in cancer therapy: an update

“…Similarly, other Btk inhibitors (AVL-292, RN486, CGI1746, ONO-40590) used in the combination with 5-FU also inhibited the growth of these cells via enhancement of apoptosis. Moreover, a cytotoxic response was obtained on patient-derived 3D organoids after the administration of 5-FU with ibrutinib or AVL-292 [182]. In the mouse xenograft model resensitization to 5-FU in HCT116p53KO cells in the presence of ibrutinib was observed [182].…”

“…Moreover, a cytotoxic response was obtained on patient-derived 3D organoids after the administration of 5-FU with ibrutinib or AVL-292 [182]. In the mouse xenograft model resensitization to 5-FU in HCT116p53KO cells in the presence of ibrutinib was observed [182]. In turn adding erythropoietin to LFM-A13 (Btk inhibitor) significantly intensified the anticancer action of LFM-A13 in colon cancer xenografts [183].…”

Harnessing Omics Approaches on Advanced Preclinical Models to Discovery Novel Therapeutic Targets for the Treatment of Metastatic Colorectal Cancer

“…In particular, a new BTK isoform, p65BTK, has been found to be abundantly expressed in CRC where, acting downstream of the RAS/MAPK pathway, it plays a role as mediator of RAS-induced transformation [ 67 ]. Interestingly, BTK inhibition re-sensitizes drug-resistant colon cancer cell lines, organoids, and xenografts lacking TP53 in 5-fluorouracil [ 68 ]. Therefore, these evidences could suggest that BTK could be a promising new target in CRC tumors that are resistant to conventional therapy.…”