Abstract 54P
Background
The current standard-of-care treatment for refractory BRAF-V600E mutant metastatic colorectal cancer (mCRC) consists of the BRAF inhibitor encorafenib plus the EGFR inhibitor cetuximab. However, tumour responses to this regimen are mostly transient, presumably caused by a rebound in MAPK activation.
Methods
In this study, we combined short-term cell viability assays with long-term re-growth assays following drug removal over a period of three weeks which allows assessment of re-growth after therapy discontinuation. We applied this strategy to test the effect of combined BRAF inhibition (encorafenib) and EGFR inhibition (afatinib), on BRAF-V600E mutant CRC patient-derived organoids (PDOs).
Results
Combined EGFR/BRAF inhibition initially caused a major reduction in PDO growth capacity in BRAF-V600E mutant PDOs. This was followed by re-activation of MAPK and rapid re-growth after drug removal, as is observed in CRC patients. During re-growth, the insulin receptor (IR) and insulin-like growth factor receptor (IGF1R) were activated in BRAF-V600E mutant PDOs. The IGFR/IR inhibitor linsitinib prevented the rebound in MAPK activity following removal of afatinib and encorafenib, prevented re-growth of CRC PDOs, and improved the anti-tumour response in an in vivo model.
Conclusions
PDO re-growth assays allow the identification of pathways driving tumour recurrence. IR/IGFR-inhibition prevents re-growth following golden standard MAPK pathway-targeted therapy and provides a strategy to improve the treatment of BRAF-V600E mutant CRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
O. Kranenburg.
Funding
U-PORT.
Disclosure
All authors have declared no conflicts of interest.