Mechanism of non-oncogene addiction

摘要

Abstract With the advent of personalized cancer medicine, mutations in tumors can be paired with targeted therapies such as tyrosine kinase inhibitors (TKI). However, even the most potent TKI fail to eradicate all cancer cells. Subsequently, tumor-repopulating cells within minimal residual disease (MRD) contribute to patient relapse. The application of Abl-kinase inhibitors to the BCR/ABL oncoprotein in chronic myelogenous leukemia (CML) is a paradigm for personalized medicine. TKI therapy in CML leads to long lasting therapeutic benefit; however, MRD remains and can eventually evolve to blast crisis. Although the molecular mechanisms underlying the failure of TKI to eradicate CML MRD are not known, growth factor signals are suspected to replace the TKI- disabled oncoprotein survival signals. We have determined that c-Fos and Dusp1 are critical for growth-factor- mediated TKI resistance. Both genetic and chemical inhibition of Dusp1 and c-Fos render CML exquisitely sensitive to TKI, and cure a mouse model of CML. Overall, our published and preliminary data suggests that expression levels of c-Fos and Dusp1 determine the threshold of TKI efficacy during chronic CML disease. Extending this line of investigation, the proposed research will determine whether c-Fos and Dusp1 are necessary and sufficient for the evolution of CML to blast crisis, and whether c-Fos and Dusp1 levels determine response to TKI in blast crisis. Next, we hypothesize that Fos and Dusp1 signals converge upon oncogenically-activated enhancers. We propose that Fos-Jun AP-1 complexes facilitate oncogenically active enhancers, while in the absence of c-Fos and Dusp1 signals, Jun-JunD AP-1 complexes predominate but do not support tumor maintenance. Specifically, we will molecularly link c-Fos-Jun AP-1 and Dusp1 activity to global enhancer chromatin dynamics. Moreover, we will exploit chromatin-embedded target-gene-reporter alleles to provide a detailed analysis of functionally-relevant downstream genes at a single-cell level in primary CML cells. The proposed work is expected to delineate the necessity of c-Fos and Dusp1 in CML-blast-crisis TKI sensitivity, as well as to provide deep molecular insight into the mechanisms underlying blast crisis and cytokine-mediated TKI resistance. We expect that this information will be informative not only for CML and blast crisis, but also the broad group of tyrosine-kinase oncoprotein-driven tumors that are not cured by TKI.