The Impact Of Human EGFR Kinase Domain Mutations On Lung Tumorigenesis And In Vivo Sensitivity To EGFR Targeted Therapies

To understand the role of human epidermal growth factorreceptor(hEGFR) kinase domain mutations in lung tumorigenesis andresponse to EGFR targeted therapies, we generated bitansgenic micewith inducible expression in type â…¡ pneumocytes of two common hEGFRmutants seen in human lung cancer. Both bitansgenic lines developedlung adenocarcinoma after sustained hEGFR mutant expression,confirming their oncogenic potential. Maintenance of these lung tumorswas dependent on continued expression of the mutant kinases.Treatmentwith small molecule ingibitors (erlotinib or HKI-272), but not ahumanized anti-hEGFR antibody (cetuximab) led to dramatic shrinkageof these tumors independent of Ink4A/Arf status. These data suggestthat persistent EGFR signaling is required for tumor maintenance inhuman lung adenocarcinomas expressing EGFR mutants.The somatic hEGFR kinase domain mutations are highly correlatedwith the clinical response to gefitinib or erlotinib therapy in lungcancer patients. Our findings that these hEGFR kinase domain mutantsare oncogenic in vivo and that their continual expression is necessaryfor tumor maintenance validate the importance of the mutated enzymeas a therapeutic target. EGFR targeted therapy against murine cancersover expressing hEGFR mutants is dramatically effective, suggestingthat these mutants are directly involved in tumor initiation and cellsurvival. The differential response in vivo of hEGFR mutant driventumors to treatment with small molecule and antibody-basedEGFR-directed agents may offer guidance in treatment selection forlung cancer patients.In particular, this study makes several major contributions:1. We show that the hEGFR kinase domain mutations are oncogenicin vivo. Using inducible bi-transgenic mouse models, we havedemonstrated that over expression of the two common hEGFRmutants(representing about 80% total EGFR kinase domain mutations)specifically in the lung compartment results in the development ofadenocarcinomas with bronchioloalveolar carcinoma(BAC) features.These murine lung tumors are very similar to human lung cancers thatharbor hEGFR kinase domain mutations and respond dramatically togefitinib or erlotinib(EGFR inhibitors) treatment.Furthermore, wehave shown that these murine tumors are dependent on the continualexpression of hEGFR kinase domain mutants for their survivalsignaling.These results solidify the importance of hEGFR kinase domainmutants as therapeutic targets.2. By breeding the Ink4A/Arf mutant allele into our bitransgenicmouse cohorts, we have also shown that Ink4A/Arf deficiency cooperateswith the hEGFR mutants to accelerate the initiation and developmentof lung tumors. However, the response of these tumors to eitherdoxycucline withdrawal or small molecule hEGFR inhibitors areindependent of Ink4A/Arf status.3. We have demonstrated that these hEGFR mutant driven tumorsare exquisitely sensitive to reversible (erlotinib) and irreversible(HKI-272) small molecule tyrosine kinase inhibitors, but are fairlyresistant to cetuximab, a humanized monoclonal antibody against EGFR.These findings may provide guidance for treatment selection for lungcancer patients harboring these hEGFR kinase domain mutations.4.These de nove lung cancer mouse models also serve as potentialplatforms for the testing of additional novel therapeutic agents andcommpounda directed against hEGFR kinase domain mutant driven tumorsin vivo. Furthermore, as demonstrated in this study, these mouse modelscan also serve as platforms to layer on additional oncogenic or tumorsuppressor alleles to determine their genetic interaction in tumorinitiation and progression as well as their impact on sensitivitiesto therapeutic interventions.