KRAS activating mutations as predictors of susceptibility to Hsp90-inhibitor-treatment
The Heat shock protein 90 (Hsp90) is part of a multichaperone complex involved in posttranslational folding of client proteins. A lot of these client proteins play essential roles in tumorigenesis. However, it is still largely unknown how Hsp90 can recognize structurally unrelated client proteins and which client protein plays an essential role in a specific tumor type. Once known, such a client-oncoprotein might be used as a marker to stratify the patient population prior to treatment with an Hsp90-inhibitor and to predict responsiveness of those patients.
Scientists from the Max Planck Institute for Neurological Research in Cologne and the Medical Faculty of the University of Cologne have developed a genomics approach to identify genetic lesions in tumor cells associated with therapeutically relevant oncogene dependency:The genomes of a large panel of human non-small cell lung cancer (NSCLC) cell lines were shown to be highly representative of those of of primary human NSCLC tumors.Using cell-based compound screening coupled with diverse computational approaches to integrate orthogonal genomic and biochemical data sets, enabled the identification of molecular and genomic predictors of therapeutic response to clinically relevant compounds.Using this approach, it could be shown that KRAS (v-Ki-ras2, Kirsten rat sarcoma viral oncogene homolog) activating mutations confer enhanced Hsp90 dependency. Cell culture data were validated in mice with KRAS-driven lung adenocarcinoma, as these mice exhibited dramatic tumor regression when treated with an Hsp90 inhibitor.
A priority application was filed on August 2009. Meanwhile a worldwide application is pending.