The management of EGFR mutant NSCLC has witnessed the development of first, second and third generation tyrosine kinase inhibitors (TKIs) reaching a substantial improvement in disease outcome. However, data on the optimal sequence of these therapies is needed.
An in vivo model of acquired resistance has been obtained by treating nude mice xenografted with the human EGFR mutant (del ex19) NSCLC cell line, HCC827, with a sequence of first, second and third generation EGFR-TKI. Mice were randomized to erlotinib or gefitinib in first line treatment; resistant tumors were re-implanted in mice and randomized to afatinib +/- cetuximab. Each first and second-generation EGFR-TKI resistant tumor was again re-implanted and randomized to osimertinib or standard chemotherapy with cisplatinum-pemetrexed.
In the first line treatment, an initial dose-dependent decrease in tumor volume with subsequent development of acquired resistance was evidenced in the majority of tumors with a response rate (RR) of 60%. In the second step, while afatinib treatment resulted in a RR of 85%, mostly represented by partial responses, the combination of afatinib plus cetuximab displayed a RR of 100% (85% complete responses). In the third step, although none of resistant tumors was T790M + , treatment with osimertinib resulted in a RR of 71% (including one complete response lasted more than 10 weeks). Chemotherapy caused predominantly stable diseases lasted less than 5 weeks. Protein and gene expression analysis on protein extracts from tumors with acquired resistance showed a progressively increasing activation of the Hedgehog pathway as compared to untreated controls in the majority of samples, with higher protein level of SMO and Gli1.
Osimertinib is effective after failure of first and second generation EGFR-TKIs, independently from the T790M presence. These experiments confirm the role of Hedgehog pathway as important mediator of resistance to EGFR inhibition.
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Second University of Naples
All authors have declared no conflicts of interest.