Previously Funded Research

Pinar Özden Eser, PhD

Eli and Edythe L. Broad Institute of MIT and Harvard

Research Project:

Identifying actionable targets to improve response to therapy among patients with HER2-driven NSCLC

Summary:

The past two decades have ushered in an era of precision medicine in the treatment of solid tumor malignancies, including non-small cell lung cancer (NSCLC). Precision therapies are informed by the genetic mutations specific to a patient’s tumor, and permit selective targeting and killing of cancer cells by small molecule inhibitors, antibody therapies that can target cell surface proteins with high affinity, or antibody-drug conjugates (ADCs). ADCs combine the specificity of antibody therapeutics and leverage cleavable linkers to deliver cytotoxic chemotherapy drugs directly to cancer cells, thereby potentiating their efficacy against malignant cells while mitigating their systemic side effects on the patient.

Although these targeted therapies improve both quality of life and survival outcomes for patients, tumor cells still frequently evolve evasion strategies, or mechanisms of resistance, which enable them to circumvent tumor cell killing by targeted therapy. The development of drug tolerance and resistance limits the duration of clinical benefit many patients can receive from targeted therapies, and necessitates the identification of mechanisms of resistance, evaluation of vulnerabilities retained in drug tolerant cancer cells, and development of next-line therapeutic interventions.

Depending on the study cohort, 5-10% of NSCLC is driven by activating mutations in the human epidermal growth factor receptor 2 (HER2) protein. HER2 is an essential protein found on the cell surface that promotes cell survival and division for healthy turnover and repair processes. However, certain mutations in the ERBB2 gene that encodes the HER2 protein, can result in over-activation of HER2, thereby driving the aberrant activation of downstream signaling cascades, causing uncontrolled cell division, and ultimately driving cancer. Mutations in ERBB2 that result in the formation of an overly active HER2 protein range from genomic amplifications, found in 2-5% of patients, to activating mutations spanning both the extracellular and intracellular domains of the protein that are vital to its activity. These mutations account for 2-4% of HER2-driven NSCLC, and can occur concurrently or separately from ERBB2 amplification. Whereas patients whose tumors are driven by ERBB2 amplification alone receive clinical benefit from small molecule and ADC HER2 targeting agents, the clinical benefits of most existing compounds for patients with ERBB2 mutant tumors have been more modest, underscoring the vital need to study this subset of patients. Given the urgent clinical need to establish a standard of care for ERBB2-mutant NSCLCs, these cancers are an active area of clinical investigation. In fact, a new small molecule therapy, zongertinib, was recently approved for the treatment of HER2-driven NSCLC that did not show response to prior rounds of therapy. The recent approval of this clinical compound, as well as the ongoing evaluation of the efficacy of HER2-targeted ADCs such as trastuzumab-deruxtecan (T-DXd), underscores the need to prioritize mechanistic studies to predict biomarkers of response and mechanisms of resistance to these compounds within the rapidly evolving landscape of HER2-mutant NSCLC treatment. Our central objective in this proposal is to understand the factors limiting the effectiveness of HER2 targeting agents in ERBB2-mutant NSCLC, and identify and validate actionable drivers of drug tolerance and resistance, with the goal of improving the efficacy of different modalities of HER2 inhibitors by identifying novel biomarkers of patient response and potential rational drug combinations to improve both progression-free and overall survival in patients with HER2-driven NSCLC.

We propose to approach these goals through three complementary Specific Aims. First, we will systematically interrogate the genomic (identifying DNA mutations) and transcriptomic (measuring RNA expression as a surrogate metric for protein expression) events underlying treatment response and resistance in pre-treatment HER2-mutant NSCLC patient samples, collected from diagnostic biopsies from patients with HER2-mutant NSCLC undergoing treatment at the MGH Cancer Center (AIM 1). Next, we will study established and patient-derived cell culture models and measure their single-agent and combination drug sensitivities to pinpoint compounds with the potential to increase sensitivity to novel small molecule (including zongertinib) and ADC (including T-DXd) HER2-targeting agents (AIM 2). Finally, we will leverage a novel molecular technology developed by our collaborators at the Broad Institute, TimeVault, to capture the RNA expression profiles longitudinally from the same cultured cells across two time points, to identify transcriptional profiles giving rise to drug tolerance, persistence, or resistance, and thereby disease progression (AIM 3).