Overcoming metastatic resistance to ErbB-targeted therapies

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Human Epidermal Growth factor receptor 2 (Her2) is overexpressed in 20-25% of breast cancers. Targeting Her2 using antibodies, kinase inhibitors and antibody-drug conjugates has improved outcomes for patients bearing this subtype of breast cancer. However, Her2-targeted therapies suffer from the drawbacks of inherent and acquired resistance, leading to metastatic disease relapse and patient lethality. Recent studies, by our lab and others have begun to establish that the mechanisms that drive metastasis are similarly essential in facilitating resistance to targeted molecular therapies. These mechanisms broadly fall under the processes of epithelial-mesenchymal transition (EMT). However, the similarities and differences between drug-induced EMT and those induced by known physiologic mediators of EMT, such as TGF-β, remain poorly defined. Therefore, the overall OBJECTIVE of the proposed studies is to identify and target molecules that are similarly regulated during metastasis-associated EMT and drug-induced EMT as a means to develop therapies that specifically target drug resistant metastases. To this end, our preliminary studies have compared the gene expression profiles generated from models of Her2-therapy resistance with our established models of metastasis that are specifically driven by TGF-β-induced EMT. This approach has yielded critical genes that are involved in cellular production and sensing of alternate growth factor pathways and the extracellular matrix. The current application focuses on fibroblast growth factor receptor-1 (FGFR1) and fibroblast growth factor-2 (FGF2), two potently upregulated genes in both Her2-therapy resistance and EMT-driven metastatic progression. Directed overexpression of FGFR1 has validated the FGF2:FGFR1 signaling axis as capable of facilitating resistance to the clinically used Her2/EGFR kinase inhibitor Lapatinib. Therefore, AIM1 of our proposal will utilize several molecular and genetic approaches to establish the transcriptional mechanisms that are responsible for EMT- driven expression of FGFR1. Members of this transcriptional network will be evaluated across patient tumor samples and correlated to patient outcome. The most recently approved Her2-targeted therapy is the antibody- drug conjugate Trastuzumab-emtansine (T-DM1). We observe T-DM1 to produce dramatic regression of established Her2+ tumors, but minimal residual disease (MRD) remains detectable by bioluminescence and after a period of dormancy eventually grows out and is resistant to T-DM1. In AIM2 we will utilize inducible models of FGFR expression to elucidate its role in the survival and eventual outgrowth of T-DM1 resistant MRD. Finally, together with our collaborators we have recently established the in vivo application of FIIN4, a novel covalent kinase inhibitor of FGFR. Therefore, in AIM3 we will continue our use of patient-derived xenografts (PDX) of Her2+ breast cancer to establish therapies utilizing this next-generation compound in combination with Lapatinib and T-DM1. These preclinical studies will establish combination therapies targeting Her2 and FGFR as capable of eradicating metastatic and primary breast cancer.