Applications

Drug Reprofiling

The small molecule drugs Iressa (Gefitinib) and Tarceva (Erlotinib) have been approved for treatment of non-small cell lung cancer (NSCLC) and; are effective in approximately 10% of patients carrying direct activating mutations in the EGFR gene (the target of these tyrosine kinase inhibitors).

In contrast, the monoclonal anti-EGFR antibodies Erbitux (Cetuximab) and Vectibix (Panitumumab) are thought to be ineffective on these same patients (Mukahora et al; Doody et al) even though they do provide benefit to colon cancer patients carrying non-mutated forms of EGFR, but are wild type for K-Ras (Benvenuti et al) or B-Raf (Di Nicolantonio et al).

Here we present data using X-MAN 1 and 2 models that firstly; a) Recapitulate the K-Ras/B-Raf pathway resistance profile present in colon cancer patients, and b) Suggest that Erbitux can elicit potent effects on mutated EGFRs (del E746-A750) when studied in a definitive isogenic cell-based system.

These data are now causing us to re-examine clinical data to understand whether there are subtleties in patient responses to EGFR-antibodies based on which type of EGFR mutation they posses and we are in the process of building additional X-MAN models to understand this further.

Cetuximab 1 Final

Figure-1: On HME EGFR-mutant X-MAN lines Erbitux is highly-sensitive (grey; EC50 0.2nM) compared to isogenic wild-type X-MAN lines (black; EC50 >333nM).  Iressa shows the same preferential sensitivity for the EGFR mutants (red; EC50 2nM) vs wild-type cells (blue; EC50 >8000nM). In the same experiment, Paclitaxel was used as a positive control (EC50 1-5nM across the panel – not shown).

Cetuximab 2 Final

Figure-2: EGFR-mutant (del 746-750) genotypes are highly-sensitive to Erbitux (red; EC50 0.2nM) compared to wild-type X-MAN lines (grey; EC50 >333nM); Secondary mutations in B-Raf or PI3K render the cells insensitive to Erbitux (blue EGFR PI3K EC50 >333nM; black EGFR B-Raf EC50 >333nM). In the same experiments, Paclitaxel was used as a positive control (EC50 1-5nM across the panel).  The same experiment was also performed on Iressa, which shows the same patterns of sensitivity and resistance across this X-MAN panel.

Excitingly, these validated models, accurately predict patient drug-sensitivity and resistance- profiles based on their tumours genetics, thus forming an ideal and definitive system to find synergistic drug combinations that reverse their K-Ras/B-Raf mediated resistance to EGFR-targeted agents.  Such combinatorial drug screens are now underway at Horizon’s research laboratories.

The availability of such data enables researchers to determine the full range of sensitive and resistant patient populations to the disease target in clinical trials. This will enable the design of smaller more efficient clinical trials that will read-out quicker, be more likely to succeed and reduce the high rate of attrition currently observed at this critical phase of drug development.

Relevant data-sets are available for each application and can be shared under confidential disclosure agreement. Please write to info@horizondiscovery.com for details

Horizon Offering
  • Horizon Discovery has a wide range of isogenic models available for immediate licensing or purchasing (Learn more) and; can also develop custom isogenic models or screen drug candidates against your specific gene target (Learn more)
References
  • Di Nicolantonio et al, 2008, Journal of Clinical Oncology, Nov, E-Pub
  • Doody et al, 2007, Mol. Can. Ther. Vol 6, p2642
  • Benvenuti et al, 2007, Cancer Research, March, 67(6), 2643-2648
  • Mukohhara et al, 2005, JNCL, Vol 87, p1185
  • Howes et al, Horizon Discovery, Internal Data, October 2008
  • Horizon Discovery Ltd. Technical Presentation (Download (6.95MB))