PD98059  In this mouse model, the forced expression of the mutant allele is capable of inducing invasive adenosquamous carcinomas that are restricted to the proximal and distal bronchioles. These cancers were completely dependent on the presence of this mutation and regressed completely when the expression of the mutant gene was reversed. Treatment with afatinib led to significant tumor regression in this preclinical model. In two of our clinical cases, the addition of paclitaxel to afatinib led to additional disease control, with prolonged remission in one patient despite a short response to single-agent afatinib, raising the possibility of synergism. In a xenograft of the HER2 mutant lung cancer cell line Compound Libraries

H1781, which contains a homozygous single amino-acid insertion in exon 20 8, administration of afatinib resulted in disease stabilization, in contrast to the tumor regression observed in the preclinical mouse model. Screening Library Taken together with our clinical experience, this indicates that the human HER2-driven lung cancer may have a more complex molecular pathogenesis than the preclinical HER2-driven mouse model. The therapeutic effect observed in Case 2 was also of considerable interest, as the tumor

High Throughput Screening  showed genomic activation of both EGFR and HER2, and was previously treated with, and had become clinically resistant to, erlotinib, trastuzumab and lapatinib 17. Although we cannot exclude that the second response, with added paclitaxel, results from the activity of single-agent paclitaxel, the magnitude and duration of the response in patients with disease resistant to multiple other chemotherapies suggests that