Drug Response and Resistance in Advanced NF1-Associated Cancers
Abstract
Juvenile myelomonocytic leukemia (JMML) and other types of myeloproliferative neoplasms (MPNs) progress to acute myeloid leukemia (AML) in a substantial proportion of patients. The NF1 gene is frequently inactivated in NF1 patients who develop either JMML or AML. However, AML is a more aggressive malignancy that invariably contains multiple additional genetic alterations that interact with NF1 loss. We have extensively characterized MPN and AML in Nf1 mutant mice and have investigated mechanisms of drug responses and resistance. Our studies of MEK inhibitors in Nf1 mutant mice with MPN and AML showed that cooperating mutations that are acquired as MPN evolves to aggressive AML increase the dependence of these cells on Raf/MEK/ERK signaling. However, drug resistant AML clones rapidly emerge in vivo. We have also shown that we can utilize this novel system to validate genes that cause resistance to MEK inhibitors. Our goal is to deploy genetically accurate mouse models of advanced NF1-associated cancers to identify mutations that cooperate with Nf1 inactivation in cancer progression, to develop a preclinical paradigm for combining conventional and targeted anti-cancer agents in vivo, and to uncover mechanisms of drug response and resistance. To date, we have generated a robust system for modulating gene expression in primary leukemia cells in vivo, have shown that treatment with CPX-351 prolongs survival of Nf1 mice, and have established an effective dose of the FDA-approved MEK inhibitor GSK1120212 (trametinib).
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2013
- Accession Number
- ADA581891
Entities
People
- Kevin Shannon
Organizations
- University of California, San Francisco