The goal of our research program is to understand the detailed mechanisms by which a cancer cell can develop resistance to therapies targeting its oncogenic driver; and to exploit those findings to elucidate the biology of cancer and identify more effective treatments for cancer patients. The focus of this work has been on signaling networks emanating from the hormone receptor, ERa, and the receptor tyrosine kinase, HER2. These two signals play a dominant role in cancers of the breast, with roughly 85% of all tumors driven by one or both of these receptors. Whereas drugs targeting these signals have major benefits in patients, resistance to therapy is frequently encountered. Our studies have centered on (1) understanding how cancers evolve to resist therapies against ER, CDK4/6, HER2, and PI3K and (2) development of mechanism-based drugs or treatment strategies that can prevent or overcome these modes of resistance. Major areas of interest include:

Estrogen driven activation of CDK4/6-cyclinD is essential for both physiologic mammary gland development as well as proliferation of ER⁺ breast tumors. This understanding has led to the development and widespread use of ATP competitive CDK4/6 inhibitors for patients with ER⁺ breast cancer. Combining these inhibitors together with antiestrogens has yielded remarkable improvements in survival over antiestrogens alone; however, intrinsic and acquired drug resistance remains a major problem while also implying the potential for improving this strategy. Using both clinical samples and cell lines exposed to drug, we have identified oncogenic signals contributing to therapy resistance via upregulation of CDK6 . We have helped resolve the biochemical basis for resistance as manifesting through a drug-insensitive CDK6-INK4 complex and developed compounds capable of overcoming this activity. These results have set the stage for several ongoing projects including: (1) using our computational models and biochemical assays to screen for novel inhibitors of the CDK6-INK4 complex, (2) optimization and development of our initial CDK6 degrader compound, (3) characterization of the biologic function of the FAT1-YAP pathway in breast cancer pathogenesis beyond its role in regulating CDK6-INK4 during therapy resistance, (4) understanding the biologic basis for long-term responders to anti-estrogen-CDK4/6i including the role of therapy induced senescence and what pharmacologic strategies might embellish this response.

HER2 directed therapy with antibodies, trastuzumab and pertuzumab, have transformed this disease from an unfavorable prognostic subtype to a more favorable one. Moreover, inhibition of mutant PIK3CA has also recently emerged as a valuable therapeutic approach for ER+ breast cancer. We have been investigating resistance to HER2/PI3K targeted therapy in both HER2+/ER- and in ER+/HER2- disease and identified alterations that reactivate PI3K/AKT signaling as well as several that activate the RAS/MAPK pathway. The latter alterations are somewhat surprising inasmuch as we have shown that the PI3K/AKT pathway is the dominant effector of oncogenic HER2 signaling. A key question that emerges from these findings is how cancer cells can evolve to change their pathway dependencies and switch oncogenic effectors (cap-dependent translation, G1-S transition, apoptosis, super enhancers, etc) from dependence on one pathway to another (e.g. PI3K to MAPK). Addressing this question should provide insights into many cancer types where such changes in the driver pathway occur, uncover biomarkers that can predict such changes, and develop strategies to target or prevent such resistance from emerging.

ESR1 mutant breast cancer. Drugs targeting estrogen synthesis including GnRH antagonists and aromatase inhibitors are the mainstay of therapy for most breast cancer patients. My laboratory helped discover and biochemically characterize constitutively active mutations in ESR1 among patients who developed resistance to these forms of therapy, demonstrated the prevalence of these mutations in ~35% of patients with ER+ metastatic breast cancer and their impact in shortening survival of patients, and identified strategies capable of overcoming mutant receptor activity. Through these efforts, we have led clinical development of next generation ER inhibitors, modeling the ESR1 mutant state, and technologies to detect these alterations earlier in the disease course. Given the progress in understanding and targeting the particular entity, we have reduced effort on this topic in recent years and our remaining major effort is to attempt to understand the biologic selection against ESR1 mutation in early stage disease using single cell methods as well as in vitro modeling. These studies may help uncover new approaches to targeting ER beyond the Ligand Binding Domain, as well as facilitate diagnostic strategies for early detection.

Other genomic alterations that promote hormone resistance. We have identified additional acquired genetic alterations such as NF1 loss and KMT2C mutation to also be associated with antiestrogen resistance. We are similarly studying the contribution of these alterations to ER regulation of the genome and potential vulnerabilities or therapeutic strategies for such cancers. Moreover, we are investigating whether parallels for these findings exist in other cancer types including resistance to androgen receptor targeting in AR+ triple negative breast cancer and resistance to antiestrogen therapy in ER+ endometrial cancer.

The potential to target both driver and non-driver cell surface targets on cancer cells through newly developed ADCs has transformed clinical practice in many cancer types. The specific biomarkers that will identify cancers responsive to these therapies, the biologic basis for resistance to ADCs, and the strategies to enhance target expression and ADC antitumor effects are largely unknown. I have led the development of an interdisciplinary ADC working group crossing tumor types, targets, and bridging the lab and clinic to lead research into this area. Major projects are seeking to: (1) develop novel pathologic tools such as digital spatial profiling and machine learning to identify ADC-sensitive cancers, (2) determine the basis for resistance to ADCs focusing the target, linker, and payload, (3) develop a functional assay of ADC internalization to optimize patient selection, (4) study strategies to modulate receptor trafficking to enhance therapeutic index for ADCs.

An overarching finding of our work has been the capacity for breast tumors to adapt and manifest therapy resistance through the acquisition of new genetic alterations. This inherent evolvability of the lethal forms of breast cancer underlies the inability to cure them.  We have begun investigations into the sources of genomic instability in these tumors that helps to give rise to such genetic alterations and identified the APOBEC family of cytidine deaminases as a key source of mutation. Our current studies are aimed at (1) developing state of the art tools to detect APOBEC activation early in the course of breast cancer therapy before resistance emerges, (2) understanding the regulation of APOBEC activities that ultimately promote resistance to targeted therapies in breast cancer, and (3) developing synthetic lethal approaches to eradicating APOBEC-proficient tumor clones.

Undoubtedly the durable and effective therapy of the complex collection of diseases known as breast cancer will require multi-disciplinary approaches into cancer science. To facilitate these efforts, we are committed to developing several platforms for translational research that serve to accelerate research in various disciplines such as cancer microenvironment, immunology, metabolism, and metastatic spread alongside the work my lab conducts on cancer drivers and therapeutics. Major areas of investment have come in the areas of circulating biomarkers for minimal residual disease detection/intervention and treatment monitoring, patient derived modeling of breast cancer, and comprehensive genomic profiling of cancer and normal tissues.