The identification of a gatekeeper mutation

The identification of a gatekeeper Erlotinib also suggests that alternative DDR2 inhibitors may be required to overcome acquired resistance. Additional DDR2 inhibitors that have been isolated include the recently identified alkaloid natural products discoipyrroles A-D and the chemotherapeutic Actinomycin D, although the mechanism of action of these compounds is less well characterized and it is not clear if the T654I mutant would be susceptible to inhibition.42, 43, 44 The Gray group has recently developed selective inhibitors against both DDR1 and DDR2 based on a scaffold for type II kinase inhibitors primarily for use as chemical biology tools for functional studies. These tools will be invaluable in the dissection of mutant DDR2 function in lung SCC progression. Furthermore, these compounds provide the foundation for second generation DDR2 selective inhibitors that have the potential to minimize toxicities seen in multitarget tyrosine kinase inhibitors such as dasatinib. A recent report of a phase II dasatinib trial in lung SCC patients was discontinued because of excess toxicity, including the development of grade 2 pleural effusions. In addition to DDR2, dasatinib is a broadly specific tyrosine kinase inhibitor that targets BCR-ABL, SRC, PDGFR, c-KIT, and DDR1 among others., These additional targets may be responsible for the excess adverse effects observed in patients which may be overcome by more selective DDR2 inhibitors. In addition to targeted inhibitors, a chemical proteomic screen has also identified DDR2 as a client protein of the HSP90 chaperone and is susceptible to protein degradation by HSP90 inhibitors. The potency of this class of inhibitors to specific DDR2 mutants has yet to be established but previous work on epithelial growth factor receptor mutants, and the EML4-ALK translocation in lung adenocarcinoma would suggest that HSP90 inhibitors may preferentially degrade DDR2 mutants and could have utility as a potential therapeutic in lung SCC.,
CONCLUSION
ACKNOWLEDGMENTS