Overcoming Resistance to Targeted Therapy in Breast Cancer

PROJECT SUMMARY Therapies directed against lineage and oncoprotein drivers in breast cancer have led to major improvements in clinical outcomes, establishing the significance of these drug targets. In metastatic breast cancer, eventual resistance to these drugs is unfortunately common and represents a major clinical dilemma. We have focused our research efforts on understanding resistance to therapies against the major targets in luminal breast cancer including ER, HER2, PI3K, and CDK4/6. Using a combination of clinic-genomic analyses, advanced breast cancer modeling, and pharmacology, we have identified and characterized common resistance mechanisms such as ESR1 mutations driving endocrine resistance, PTEN loss promoting insensitivity to PI3Ki, and HIPPO pathway alterations and TP53 loss promoting CDK4/6i resistance. Even as these studies have paved the way towards new biomarkers such as ESR1 ctDNA as well as new therapies such as oral SERDs, they have pointed to a deeper challenge of breast cancer plasticity that underlies these acquired genetic alterations. So, despite patients being treated with 2nd generation inhibitors or combinations, we are observing new forms of resistance emerge. However, not all cases of metastatic breast cancer harbor this level of plasticity and there now also exists a growing cohort of patients with long-term disease control that must be understood in comparison. In this next phase of research into therapy resistance, we aim to elucidate the processes underlying plasticity and the resulting therapy resistance centering on three broad questions. First, by what mechanisms do discrete forms of genomic instability such as homologous recombination deficiency or APOBEC3 mutagenesis contribute to therapy resistance. Second, by what effector pathways and mechanisms of cancer cell elimination do we observe durable, long-term response to targeted therapies in subsets of metastatic breast cancer. Third, through which aspects of the antibody-linker-payload construct of Antibody Drug Conjugates do breast cancers develop resistance. The overall goal of this project is to establish the underlying mechanisms of response and resistance to modern targeted therapy in breast cancer and use these insights to develop curative approaches for increasing segments of this common disease.