Abstract C113: Modeling cetuximab clinical trial by conducting in vivo efficacy evaluation in large panel CRC patient-derived xenograft (PDX) models.

Patient derived xenograft (PDX) models without in vitro manipulation mirror patients' histopathological and genetic profiles1,2. This has the potential to significantly improve the predictive power of preclinical cancer animal models, and more importantly to enable the identification of predictive biomarkers for targeted therapeutics.

In this study, we set out to mimic a small size clinical trial by testing cetuximab in a large cohort of CRC models. Among 19 CRC models tested, 7 models were found sensitive (37%) and 12 resistant (63%) to cetuximab. All 3 models with BRAF activating mutation are found resistant to cetuximab. Of the 11 models with KRAS activating mutation, the response profile is more complex, with 6 models resistant and 5 models responsive to cetuximab. It is interesting that 3 out of the 4 models with G13D mutation are sensitive to cetuximab. Of the 5 models which harbor neither KRAS nor BRAF mutation, 3 models are resistant, suggesting that other oncogenic drivers are involved. Interestingly, one of the resistant models harbors an EGFR R776H activating mutation.

The observation that KRAS mutations such as G13D and G12C are still sensitive to cetuximab, although contrary to the accepted dogma that CRC patient with mutant KRAS does not benefit from cetuximab3, is consistent with the recent findings in clinic4–7. Other KRAS mutations such as A146T and R61H were found in the resistant models, may imply that mutations besides codon 12 and 13 can play roles in the pathogenesis of CRC and the drug resistance. The overall resistant profile of models with BRAF mutation may also suggests another potential risk factor which warrants further investigation.

In summary, our results have demonstrated that large panel HuPrime® can be used to effectively evaluate investigational new drugs for efficacy prediction and to discover predictive biomarkers to guide patient stratification for clinical development.

References

1. E. Marangoni et al., Clin Cancer Res 13, 3989, 2007.

2. L. Ding et al., Nature 464, 999, 2010.

3. A. Lievre et al., Cancer Res 66, 3992, 2006.

4. W. De Roock, V. De Vriendt, N. Normanno, F. Ciardiello, S. Tejpar, Lancet Oncol 12, 594, 2011.

5. W. De Roock et al., JAMA 304, 1812, 2010.

6. W. De Roock et al., Lancet Oncol 11, 753, 2010.

7. R. Kirk, Nat Rev Clin Oncol 8, 1 2011.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C113.