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Rethinking Gamma-Secretase Inhibitors for Treatment of Non-Small Cell Lung Cancer: Is Notch the Target?

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Rethinking Gamma-Secretase Inhibitors for Treatment of Non-Small Cell Lung Cancer: Is Notch the Target? Author Manuscript Published OnlineFirst on August 13, 2018; DOI: 10.1158/1078-0432.CCR-18-1635 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Rethinking gamma-secretase inhibitors for treatment of non-small cell lung cancer: Is Notch the target? Sharon R. Pine, Ph.D. Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA Department of Pharmacology and Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA Running title: Rethinking gamma secretase inhibitors Keywords: gamma secretase inhibitor, Notch, patient-derived xenograft, non-small cell lung cancer, targets Corresponding Author: Sharon R. Pine, Ph.D., Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901. Phone (732) 235 9629; Fax (732) 235 8096; E-mail: [email protected] Support: This research was supported by the National Cancer Institute (NCI), National Institutes of Health (NIH) (R01CA190578 to SRP). Conflict of interest statement: None to disclose Word count: Translational Relevance, 116; Abstract, 217; Manuscript, 2,522 Number of figures: 1 figure 1 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 13, 2018; DOI: 10.1158/1078-0432.CCR-18-1635 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Translational Relevance Non-small cell lung cancer is responsible for one-fourth of cancer deaths. Although targeted therapy is available for a subset of patients and immunotherapy has recently become a standard- of-care, the death toll due to NSCLC has not decreased much. We discuss the need for additional therapies, focusing on ɣ-secretase inhibitors, a class of small molecule compounds that are most commonly known for inhibiting the Notch pathway. We propose that Notch pathway mutations may not always be the intended target for ɣ-secretase inhibitors and furthermore, that other targets may serve as better biomarkers. Diligent identification and validation of the biomarkers that confer sensitivity to ɣ-secretase inhibitors are needed in order to continue clinical trials on molecularly selected patients. 2 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 13, 2018; DOI: 10.1158/1078-0432.CCR-18-1635 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Lung cancer is the leading cause of cancer deaths among men and women. Gamma-secretase inhibitors, a class of small molecule compounds that target the Notch pathway, have been tested to treat non-small cell lung cancer (NSCLC) in pre-clinical and clinical trials. Although ɣ- secretase inhibitors elicit a response in some tumors as single agents and sensitize NSCLC to cytotoxic and targeted therapies, they have not yet been approved for NSCLC therapy. We discuss our recently published pre-clinical study using the ɣ-secretase inhibitor AL101, formerly BMS906024, on cell lines and PDX models of NSCLC, primarily lung adenocarcinoma. We propose that Notch pathway mutations may not be the most suitable biomarker for predicting NSCLC response to ɣ-secretase inhibitors. Gamma-secretases have over 100 known γ‐secretase cleavage substrates. Many of the ɣ-secretase substrates are directly involved in carcinogenesis or tumor progression, and are ideal candidates to be the “on-target” biomarkers for ɣ-secretase inhibitors. We propose the need to systematically test the ɣ-secretase and other targets as potential biomarkers for sensitivity before continuing clinical trials. Now that we have entered the post-genome/transcriptome era, this goal is easily attainable. Discovery of the biomarker(s) that predict sensitivity to ɣ-secretase inhibitors would guide selection of the responder population that is most likely to benefit and move the compounds closer to approval for therapeutic use in NSCLC. 3 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 13, 2018; DOI: 10.1158/1078-0432.CCR-18-1635 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Current treatment of non-small cell lung cancer The American Cancer Society has estimated that there will be 234,030 new cases of lung cancer and 154,050 deaths due to lung cancer in the United States in 2018, which ranks as the highest cause of deaths among all cancers for men and women [1]. Non-small cell lung cancer (NSCLC) accounts for 80 – 85% of patients with lung cancer. In early stages of the disease, patients are eligible for surgery that may be curative. Approximately 57% of NSCLC are metastatic [2], and until recently, these patients typically received platinum-based doublet chemotherapy or other two-drug combinations with only a 5% 5-year survival rate [3]. Recent breakthroughs in the use of immune checkpoint inhibitors in combination with chemotherapy or the use of targeted therapies have changed how advanced lung cancer patients are treated. Several immune checkpoint inhibitors have gone through clinical trials. The US Food and Drug Administration approved the use of pembrolizimab, an anti-PD1 inhibitor, for frontline treatment of all patients with metastatic non-squamous NSCLC who lack actionable mutations [4]. Based on the results of the phase III KEYNOTE-407 trial (NCT02775435), pembrolizumab may be approved for frontline treatment of metastatic lung squamous cell carcinoma soon. The addition of pembrolizumab to standard chemotherapy in unselected advanced-stage non-squamous NSCLC patients increased the median progression-free survival from 9 to 13 months [5]. The objective response rate for the group receiving pembrolizumab in addition to chemotherapy increased from about 30% in the chemotherapy-only group to 55%. Although these improvements are impressive when compared to historical advances, they highlight the fact that not all patients will benefit from the therapy. Frontline targeted therapies are available for NSCLC patients with a BRAF V600E mutation, or patients with features of lung adenocarcinoma (LUAD) harboring actionable driver mutations in EGFR, or fusions involving ALK or ROS1. Unfortunately, the 4 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 13, 2018; DOI: 10.1158/1078-0432.CCR-18-1635 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. nearly universal development of drug resistance has limited the success of targeted therapy [6]. This underscores the need to further refine the biomarkers for predicting the efficacy of immune checkpoint inhibitors and targeted therapies, and efforts are underway to address this on many fronts. The current state of NSCLC treatment overall highlights the urgent need to consider other strategies and to continue identifying impactful agents. ɣ-secretase and ɣ-secretase inhibitors Gamma secretase is a fascinating, multisubunit protein complex. Its catalytic core sits in the intramembrane space and facilitates the cleavage of single-pass transmembrane receptors, usually triggered by external signals. The ɣ-secretase complex comprises a catalytic subunit, called presenilin (PSEN1 and PSEN2), that works in concert with three other proteins, anterior pharynx defective 1 (APH1), presenilin enhancer 2 (PEN2), and Nicastrin [7, 8] (Fig. 1). Over 100 γ‐secretase substrates have been identified to date, including the four well-characterized mammalian Notch receptors (Notch1‐4) and the five canonical transmembrane Notch ligands [7]. Notch signaling, which has been reviewed elsewhere [7], is an evolutionarily conserved pathway that is crucial for the development and homeostasis of most tissues, and that has been implicated in cancer. The most commonly known substrate of gamma secretase is amyloid precursor protein (APP) that, when cleaved by ɣ- and β-secretase, produces a short peptide called β-amyloid. The abnormally folded fibrillar form of β-amyloid is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients [9]. Gamma secretase also cleaves many type- I transmembrane proteins that have a known functional role in cancer, such as E-Cadherin, CD44, DCC (deleted in colorectal cancer), IGF1R (insulin-like growth factor receptor), VEGF- R1 (vascular endothelial growth factor receptor), the receptor tyrosine kinase ErbB4 (a.k.a., 5 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 13, 2018; DOI: 10.1158/1078-0432.CCR-18-1635 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. HER4), as well as numerous cytokine receptors involved in tumor progression including interleukin-6 receptor (IL-6R) and IL-1R [10]. Gamma secretase inhibitors (GSI) are a class of small-molecule inhibitors that, as the name implies, prevent the cleavage of γ‐secretase substrates. A number of GSIs were developed after γ‐secretase was identified as an enzyme responsible
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