Project 4: Therapeutic Targeting of Replication Stress Vulnerabilities in Small Cell Lung Cancer

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Project 4 Project Summary/Abstract The goal of this project is to develop novel, synthetic lethal, replication stress related, approaches for SCLC patients based on their tumor’s molecular profiles. There are two major unmet needs for SCLC therapy: first, the majority of patients will experience primary or acquired resistance to clinically available chemotherapy and immunotherapy; and second, despite new data supporting molecularly and biologically distinct subsets of SCLC, there are no established approaches for biomarker-driven personalized treatments (such as is standard for targetable oncogenic drivers in NSCLC). Many of the currently “undruggable” oncogenic changes that are common in SCLC promote tumorigenesis through replication stress (RS) and genomic instability. These “hallmarks of cancer” lead to high tumor mutational burden and chromosomal aberrations. SCLCs have a continuous high degree of RS due to the universal loss of p53 and RB1 function, and frequent activation of oncogenes such as MYC. In the presence of RS, cancer cells depend on RS responses (RSR), which are a branch of DNA damage repair responses (DDR), to resolve DNA damage and stalled replication forks. Several RSR inhibitors are in clinical development, and we have preliminary findings in preclinical models indicating that SCLC lines, xenografts, and genetically engineered mouse models (GEMMs) are sensitive to agents that target RSR or that increase RS or genomic instability beyond tolerable levels. The latter group includes aurora kinase inhibitors (which induce mitotic catastrophe in the setting of high RS levels, as well as directly inhibiting DNA repair and decreasing replication fork stability) and 6-thio-dG (distinct from the well-known drug 6 thioguanine) which is incorporated by telomerase positive cells, leading to telomere disruption, and increased RS. Furthermore, we have recently found that therapeutic targeting of RS (e.g., by inhibitors of Chk1 or PARP) increases cytoplasmic DNA, resulting in activation of the innate immune response (via the Stimulator of Interferon Genes [STING] pathway), immune-mediated cytotoxicity, and enhanced response to immune checkpoint blockade. We hypothesize that: 1. RS targeting (through Aurora Kinase inhibition or telomere disruption) will lead to synthetic lethality in molecularly-defined subsets of SCLC (Aim 1); and 2. that RS targeting will enhance response to immune checkpoint blockade in immunotherapy-refractory subsets of SCLC via activation of the innate immune system (Aims 2 and 3). Specifically, we expect that RS-targeted therapies will lead to replication catastrophe and cell death in oncogene-driven lung cancers and enhance responses to immune checkpoint blockade (e.g., anti-PD-L1). We will test our hypotheses in an extensive panel of molecularly characterized SPORE lung cancer cell lines, patient derived xenografts (PDXs, tumor and circulating tumor cell (CTC)-derived), GEM-derived animal models (Aims 1 and 2), and in clinical specimens from an investigator-initiated Phase 2 clinical trial (Aim 3) of Aurora Kinase inhibition combined with checkpoint inhibitor immunotherapy in extensive- stage SCLC.