ADAM17: a potential regulator of resistance to EGFR targeted therapies in RAS wild type colorectal cancer.


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Jessica-Anne Weir1,Peter Gilliland1,Marc-Aurel Fuchs1,Rich Williams1,Liam Murray1,Patrick Johnston1,Sandra Van Schaeybroeck1
1CCRCB, Queen's University Belfast

Abstract

Background

The EGFR mAb cetuximab have been approved for the treatment of RAS wild type (WT) colorectal cancer (CRC). Mutations in BRAF, PIK3CA and/or PTEN loss, HER2 amplifications and decreased mRNA levels of the EGFR ligands epiregulin and amphiregulin have been associated with resistance to cetuximab treatment in RASWT patients. No resistance mechanisms have been identified for the remaining 20% of RASWT cetuximab-unresponsive patients. EGFR ligands are synthesized as transmembrane precursors that can be cleaved by members of the ADAM (a desintegrin and metalloprotease) family. We have previously identified ADAM17 as a major regulator of resistance to chemotherapy treatment in CRC. The aim of this project is to investigate a potential role for ADAM17 in regulating resistance to cetuximab treatment in RASWT CRC.

Method

A panel of RASWT CRC cells were used. RASWT-cetuximab resistant CRC cells were generated by repeated exposure to stepwise increasing concentrations of cetuximab over a period of 3m. MTT and Western blotting was used to measure cell viability and apoptosis, ELISA, RT-PCR and ADAM17 activity assay to measure EGFR ligands and ADAM17 activity levels respectively. The ADAM17 inhibitor IK682 was generated in the chemistry lab.

Results

Treatment of RASWT CRC cells with the EGFR mAb resulted in significant increases in ADAM17 activity. Moreover, addition of rhTGF-α to the culture medium of RASWT cells, resulted in significant decreased sensitivity to cetuximab treatment. Co-treatment of cetuximab with IK682 resulted in potent synergy in a panel of RASWT CRC cells. Preliminary data showed increased activity of c-MET and STAT3, but not EGFR, in our RASWT cells with acquired resistance to cetuximab treatment. In addition, RASWTcetR showed resistance to IK682, alone and when combined with cetuximab treatment.

Conclusion

These data would suggest that ADAM17 may play a role in primary, but not secondary resistance to cetuximab treatment in RASWT CRC.

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