<p dir="ltr">Metastatic breast cancer (BC) remains a dauting therapeutic challenge due to the heterogeneity and cellular plasticity that exists. Because of these, BC resistance to targeted therapies and immune checkpoint blockade (ICB) present major challenges in the clinical setting. As a result, incomplete clearance of BC during a therapeutic regimen can lead to the persistence of minimal residual disease (MRD) which greatly contributes to tumor relapse. Here we develop a powerful in vivo model of lung metastasis in which we can achieve robust pulmonary tumor regression in response to the fibroblast growth factor receptor (FGFR) inhibitor, pemigatinib.</p><p dir="ltr">To enhance the efficacy of ICB, tumors must first be converted from an immune “cold” environment to an immune “hot” environment. Using our in vivo model of lung metastasis, we demonstrated that pemigatinib can significantly increase the presence of infiltrating T-cells into the lungs while suppressing the presence of MDSCs both locally in the lungs and systemically. Taken together, pemigatinib is an ideal candidate to prime these immune “cold” tumors for combination with ICB.</p><p dir="ltr">Upon establishment of MRD by pemigatinib in our in vivo model we observe upregulation of an alternate growth factor receptor, platelet-derived growth factor receptor (PDGFR). Functionally, upon FGFR inhibition, there is increased response to pulmonary fibroblast derived PDGF ligand, fueling survival of MRD. We demonstrated that knockdown of PDGFR significantly delayed tumor growth reinitiation in an in vitro 3D culture following pemigatinib as well as delayed tumor relapse in our pulmonary metastasis model.</p><p dir="ltr">To limit cellular plasticity and reduce survival of MRD, we propose a novel dual-targeted approach utilizing pemigatinib, in conjunction with inhibition of DNMT1 using the reversible inhibitor GSK3484862. We used our in vivo model of lung metastasis after treatment with pemigatinib as a model of cellular plasticity to targeted therapy. This combination therapy prevented growth factor plasticity and delayed tumor recurrence. Through prevention of PDGFR upregulation induced by pemigatinib.</p><p dir="ltr">In the present dissertation works, our study demonstrates pemigatinib’s robust ability to increase infiltrating T-cells in addition to its strong antitumor effects on pulmonary tumors. Despite the robust effects of pemigatinib, acquired mechanism of resistance through upregulation of PDGFR allows survival of MRD and are supported by PDGF secreting fibroblasts. Using an approach of limiting cellular plasticity through DNA methylation inhibition combined with pemigatinib, we achieved a more durable therapeutic response. Our findings underscore the significance of understanding adaptive responses to targeted therapies and provide a tangible therapeutic strategy to prolong treatment response in metastatic breast cancer.</p>