Impact of KRAS mutations on effector mechanisms of EGR antibodies

• Applicant: Professor Dr. Thomas Valerius
• Subject Area: Hematology, Oncology
• Term: from 2009 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 128921112

The concept of personalized tumor therapy may contribute to further improvements in oncology. Important for this concept is the identification of biomarkers, which allow predicting response to or resistance against targeted therapies. Thus, mutated KRAS genes in tumor cells are associated with lack of response to the currently approved therapies against the epidermal growth factor receptor (EGFR). However, the underlying mechanisms are incompletely understood by which activated KRAS impairs effector mechanisms of EGFR inhibitors. Own results from the on-going project demonstrate that the activating KRAS-G12V mutation triggers C/EBPbeta-dependent downregulation of EGFR expression. Thereby, activated KRAS impairs both direct and interestingly indirect effector mechanisms of EGFR antibodies. Modifications in the Fc part of EGFR antibodies (Fc engineering) can partially overcome this KRAS- mediated inhibition. However, low EGFR expression levels were demonstrated to represent an independent negative predictive biomarker in lung cancer and may have broader relevance for the efficacy of antibody therapy. Recent data from clinical studies demonstrate that the G13D mutation in KRAS is not associated with lower response rates to EGFR antibodies.Against this scientific background additional experiments shall address the impact of mutated KRAS on the efficacy of EGFR antibodies during the second phase of this proposal. In particular, the impact of the G13D mutation shall be investigated in comparison to the G12V mutation, which may reveal important insights into the mechanisms underlying KRAS- mediated resistance against EGFR- directed therapies. Additionally, immunotherapeutic strategies will be developed against KRAS- mutated tumor cells - considering the reduced EGFR expression levels in KRAS- mutated tumor cells. Thus, EGFRvIII- specific scFv- fragments shall be employed to deliver small regulatory siRNA or microRNA molecules into tumor cells, which shall increase the susceptibility of tumor cells against apoptosis. Thereby, the response of KRAS- mutated tumor cells against EGFR- directed antibody therapies shall be improved. In conclusion, we expect to obtain additional insights into the mechanisms of KRAS- mediated resistance against EGFR- directed tumor therapy by continuing this project and hope to develop innovative strategies to overcome this resistance. Since KRAS mutations are prevalent in many epithelial tumors, these results may become broadly relevant for EGFR- directed tumor therapies.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Matthias Peipp