Evaluation of PARP7 dependency as a novel therapeutic target for non-small cell lung cancer

Va Greater Los Angeles Healthcare System, Los Angeles CA

Investigators

Abstract

ABSTRACT Environmental exposure and tobacco use among US Veterans operate together to increase their lung cancer risk. Despite significant progress in tumor- and immune-targeted therapies, lung cancer remains the leading cause of cancer death in US Veterans, the US and worldwide. Non-small cell lung cancer (NSCLC) comprises approximately 85% of all lung cancers. Identifying and evaluating novel therapeutic targets in NSCLC that could simultaneously harness tumor-intrinsic and host immune-mediated mechanisms to promote antitumor responses could have a major impact on treatment and clinical outcomes. Our integrated bioinformatics analyses identified PARP7 Poly (ADP-Ribose) Polymerase 7 (PARP7) as a candidate therapeutic target with an estimated 40% dependency in NSCLC. A recent study further demonstrated that targeting PARP7-dependency elicited potent antitumor effects through both tumor-autonomous and host immune-stimulatory mechanisms via enhanced type I interferon (IFN) signaling. However, the prevalence of PARP7-dependency in NSCLC primary tumors is not known, and current clinical trials of a PARP7-specific inhibitor, RBN-2397, are not guided by assessment of PARP7-dependency. There is no diagnostic platform to assess the status of PARP7-dependency, which is not driven by oncogenic mutations. It is not known whether type 1 IFN signaling is the predominant mechanism that drives the biology of PARP7 inhibition. PARP7 has been implicated as a critical factor to maintain the stemness of embryonic stem (ES) cells, while the role of PARP7 in cancer stem cells (CSCs) has not yet been elucidated. Our preliminary studies reveal that RBN-2397 induces transcriptome changes in PARP7-dependent human NSCLC cell lines, patient-derived organoids (PDOs) from NSCLC surgical specimens as well as our murine NSCLC models. These genes include both IFN downstream genes and genes implicated in cancer stemness, inflammation, cell proliferation and apoptosis, which may serve as novel mediators of PARP7 inhibition-induced antitumor effects. Our pilot single cell RNA-sequencing (scRNA-seq) studies with PARP7-dependent human NSCLC cell lines demonstrated the feasibility of utilizing the scRNA-seq approach to identify common gene signatures. In this proposal, we aim to accomplish the following objectives, utilizing both NSCLC surgical biospecimens and our novel murine NSCLC models: 1) Reach a clinically relevant estimate of PARP7- dependency in NSCLC; 2) Develop a diagnostic platform for the assessment of PARP7-dependency that is sensitive and clinically translatable; 3) Understand the mechanism of PARP7 inhibition-induced antitumor effects via type 1 IFN signaling as well as potentially novel mediators. We will evaluate the prevalence of PARP7-dependency in NSCLC by both PARP7 CRISPR fitness assays and response to RBN- 2397, utilizing both primary tumor cells and PDOs derived from primary NSCLC samples. We will utilize NSCLC surgical specimens with established PARP7-dependency to develop a scRNA-seq-based diagnostic platform that combines both functional readout of drug cytotoxicity and transcriptome signatures. We will define both type 1 IFN pathway-mediated and novel mechanisms of PARP7 inhibition-induced antitumor responses in NSCLC, including tumor cell-autonomous, host immune-stimulatory, and CSC-mediated effects, utilizing PDOs and murine NSCLC models. Findings from these studies will provide a better understanding of the prevalence and mechanisms of PAPR7-dependency in NSCLC, and facilitate future clinical evaluation of targeting PARP7- dependency as a novel treatment strategy for NSCLC.