Ulrich Guertler

HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy

Mutations in the HER2 kinase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2YVMA) in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2YVMA is essential for tumor maintenance, suggesting a key role for HER2 in lung adenosquamous tumorigenesis. Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2YVMA transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage. Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways. Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.

Discovery of novel amino-pyrimidine inhibitors of the insulin-like growth factor 1 (IGF1R) and insulin receptor (INSR) kinases; parallel optimization of cell potency and hERG inhibition

The insulin-like growth factor-1 receptor (IGF1R) and closely related insulin receptor (INSR) are receptor tyrosine kinases which have been postulated to play a role in the tumorigenesis of certain cancers. Strategies for inhibiting oncogenic signalingvia the IGF1R and INSR include IGF1R antibodies, IGF1/2 antibodies and dual IGF1R/INSR tyrosine kinase inhibitors (TKIs). IGF1R/INSR TKIs linsitinib (OSI-906) and BMS-754807 have progressed to phase II/III clinical studies in cancer patients. We describe here our efforts to develop small molecule dual inhibitors of the IGF1R/INSR receptor kinases based on an amino-pyrimidine structural class. Our main focus was the parallel optimization of cellular potency and off target activity (principally hERG inhibition) through modulation of physicochemical properties and introduction of key structural motifs using a matched molecular pairs approach and hERG homology model.