Agents In Non-small Cell Lung Cancer Research Articles

Repurposing Antiviral Drugs as Potential Anti-EGFR Agents in NSCLC: A Structure-Based Screening and Molecular Dynamics Analysis.

One of the problems resulting from recurrent hyperactivated or mutant epidermal growth factor receptors (EGFR) in non-small cell lung cancer (NSCLC) is therapeutic resistance. Consequently, this leads to increased expressionof oncogenicproteins and reduces the efficacy of EGFR tyrosine kinase inhibitors (TKIs). This study assessed antiviral drug efficacy as potential anti-EGFR agentsfor NSCLC. We used structure-based virtual screening to evaluate 66 antiviral drugs thoroughly. The top 6 antiviral drugs exhibiting impressive binding energies (i.e. surpassing a threshold of -8.5 kcalmol-1) were identified. Subsequent bioactivity analysis and ADMET profiling were performed to select the most promising candidates, followed by a molecular dynamic simulation. Among the selected antiviral regimens, dolutegravir demonstrated the highest docking score (-9.8 kcalmol-1), followed by rilpivirine and ensitrelvir, surpassing other candidates and our reference EGFR TKI. Further molecular dynamics simulations revealed promising dynamic interactions of dolutegravir, ensitrelvir, and rilpivirine with the EGFR target as compared with afatinib. Our findings highlight the repositioning potential of antiviral drugs for anti-EGFR drug discovery, supported by their robust docking scores, ADMET profiles, dynamic interactions, and binding free energies. The results open up new avenues for advanced NSCLC therapy. Further in vitro investigations are warranted to evaluate their efficacy and safety.

Polydatin, a potential NOX5 agonist, synergistically enhances antitumor activity of cisplatin by stimulating oxidative stress in non‑small cell lung cancer.

Non‑small cell lung cancer (NSCLC) is one of the major causes of cancer‑related death worldwide. Cisplatin is a front‑line chemotherapeutic agent in NSCLC. Nevertheless, subsequent harsh side effects and drug resistance limit its further clinical application. Polydatin (PD) induces apoptosis in various cancer cells by generating reactive oxygen species (ROS). However, underlying molecular mechanisms of PD and its effects on cisplatin‑mediated antitumor activity in NSCLC remains unknown. MTT, colony formation, wound healing analyses and flow cytometry was employed to investigate the cell phenotypic changes and ROS generation. Relative gene and protein expressions were evaluated by reverse transcription‑quantitative PCR and western blot analyses. The antitumor effects of PD, cisplatin and their combination were evaluated by mouse xenograft model. In the present study, it was found that PD in combination with cisplatin synergistically enhances the antitumor activity in NSCLC by stimulating ROS‑mediated endoplasmic reticulum stress, and the C‑Jun‑amino‑terminal kinase and p38 mitogen‑activated protein kinase signaling pathways. PD treatment elevated ROS generation by promoting expression of NADPH oxidase 5 (NOX5), and NOX5 knockdown attenuated ROS‑mediated cytotoxicity of PD in NSCLC cells. Mice xenograft model further confirmed the synergistic antitumor efficacy of combined therapy with PD and cisplatin. The present study exhibited a superior therapeutic strategy for some patients with NSCLC by combining PD and cisplatin.

Allicin-Mediated Cell Cycle Regulation Reverses Taxol Resistance in NSCLC: Molecular Insights and Therapeutic Potentia

The clinical efficacy of non-small-cell lung cancer (NSCLC) treatment is significantly hindered by Taxol resistance, demanding the exploration of novel approaches to overcome this challenge. Natural products, renowned for their diverse anticancer potential, offer hope, with allicin emerging as a captivating contender. However, the intricate role and underlying mechanisms of allicin in NSCLC Taxol resistance remain largely unexplored. In this extensive investigation, we delve into the impact of allicin on Taxol resistance, meticulously examining both in vitro and in vivo scenarios. Remarkably, allicin effectively curbs the proliferation and migration of A549/Taxol cells while inducing apoptosis. Unraveling the regulatory potential of genes like CDK1 in the cell cycle pathway, allicin demonstrated the ability to arrest cells in the G2/M phase, thus disrupting the cell cycle and heightening Taxol sensitivity. Strikingly, when combined with Taxol, allicin showed the ability to promote Taxol to inhibit tumor growth and reduce lung nodules in tumor-bearing mice, all without significant toxicity. Importantly, allicin’s prowess in reversing Taxol resistance via cell cycle regulation sheds light on its potential as a resistance-reversing agent in NSCLC, marking a vital milestone in the quest for natural source therapies.

Current status of clinical trial research and application of immune checkpoint inhibitors for non-small cell lung cancer.

Immunotherapy has emerged as a hot topic in the treatment of non-small cell lung cancer (NSCLC) with remarkable success. Compared to chemotherapy patients, the 5-year survival rate for immunotherapy patients is 3-fold higher, approximately 4%-5% versus 15%-16%, respectively. Immunotherapies include chimeric antigen receptor T-cell (CAR-T) therapy, tumor vaccines, immune checkpoint inhibitors, and so forth. Among them, immune checkpoint inhibitors are in the spotlight. Common immune checkpoint inhibitors (ICIs) currently in clinical use include programmed death receptor-1(PD-1)/programmed death ligand-1(PD-L1) and cytotoxic T lymphocyte-associated antigen 4(CTLA-4). This article focuses on monotherapy and combination therapy of CTLA-4 and PD-1/PD-L1 immune checkpoint inhibitors. In particular, the combination therapy of ICIs includes the combination of ICIs and chemotherapy, the combination therapy of dual ICIs, the combination of ICIs and anti-angiogenic drugs, the combination of ICIs and radiotherapy, and the combination of ICIs inhibitors and tumor vaccines and so forth. This article focuses on the combination therapy of ICIs with chemotherapy, the combination therapy of dual ICIs, and the combination therapy of ICIs with anti-angiogenic drugs. The efficacy and safety of ICIs as single agents in NSCLC have been demonstrated in many trials. However, ICIs plus chemotherapy regimens offer significant advantages in the treatment of NSCLC with little to no dramatic increase in toxicity, while combined dual ICIs significantly reduce the adverse effects (AEs) of chemotherapy. ICIs plus anti-angiogenic agents regimen improves anti-tumor activity and safety and is expected to be the new paradigm for the treatment of advanced NSCLC. Despite some limitations, these agents have achieved better overall survival rates. In this article, we review the current status and progress of research on ICIs in NSCLC in recent years, aiming to better guide the individualized treatment of NSCLC patients.

The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC.

Chemotherapy for advanced non-small-cell lung cancer (NSCLC) remains the first treatment choice. Angiogenesis inhibitors are effective for lung cancer treatment. This study explored whether chemotherapy combined with angiogenesis inhibitors could achieve better efficacy in NSCLC. The zebrafish A549 xenograft model was used to investigate the combined effect of apatinib and chemotherapeutic agents in NSCLC. Apatinib combined with pemetrexed demonstrated the highest antitumor effect compared with apatinib combined with gemcitabine or paclitaxel in vitro. In the zebrafish A549 xenograft model, apatinib and pemetrexed, alone or in combination, showed significant inhibition of tumor growth. Co-treatment with apatinib and pemetrexed demonstrated the best antitumor effects, suggesting that the combination of apatinib and pemetrexed might be a promising alternative therapy for patients with lung cancer. Apatinib combined with pemetrexed had enhanced antitumor effects compared with either one alone in the zebrafish model of NSCLC.

Comprehensive Analysis of the Expression and Clinical Significance of RAS Family Members in Non-Small Cell Lung Cancer Based on Bioinformatics Data and the A549 Cell Line Model

Lung cancer is the second most frequent worldwide diagnosed cancer. Mutations in the RAS genes family are among the most common oncogenic alterations occurring in non-small cell lung cancer (NSCLC). Many treatment options against KRAS mutations have been developed for NSCLC; however, they remain insufficient. Moreover, the role of KRAS and HRAS gene expression in lung cancer remains unclear. However, inhibitors of RAS genes expression seem to be a good candidate for new drugs agents in NSCLC. This study used bioinformatical analysis to determine KRAS and HRAS gene expression and its clinical significance, and then examined the influence of three different RAS inhibitors (farnesythiosalicylic acid (FTS), deltarasin and Kobe0065) on cell growth and the KRAS and HRAS gene expression (by RT-qPCR) in human NSCLC A549 cells. KRAS and HRAS were shown to be overexpressed in NSCLC compared to non-tumor lung tissues of healthy individuals (from databases) and significantly associated with different clinicopathological features. It was also found that FTS, in a dose-dependent manner, suppressed proliferation of human A549 cells, while deltarasin reduced expression of HRAS in the lung cancer cells. To sum up, the results obtained from analyses based on bioinformatics databases indicate that the studied genes are potential risk factors for the development of lung cancer. On the other hand, studies of their expression on cell lines indicated that they may also be potentially important in the response to treatment using RAS inhibitors.

EP08.04-002 Australian Vinorelbine Use in Advanced Lung cancer (The AVAL Study)

Immunotherapy has become a standard early line therapy for advanced non-small cell lung cancer (NSCLC). Post-progression sequencing and utilization of subsequent active therapies is of increasing importance and currently lacks expert consensus. Vinorelbine, a member of the vinca alkaloid family, is an active anti-cancer chemotherapy agent in NSCLC that may offer patients clinical benefit in this setting.

Oxidized tea polyphenol (OTP-3) targets EGFR synergistic nimotuzumab at inhibition of non-small cell lung tumor growth

Aberrant activation of epidermal growth factor receptor (EGFR) plays a pivotal role in cancer initiation and progression and has gained attention as an anticancer drug target. EGFR monoclonal antibodies have been canonically used in non-small cell lung cancer (NSCLC) treatment. However, a basal level of ligand-independent EGFR signaling pro-survival properties limit the clinical efficacy of EGFR monoclonal antibodies. Therefore, targeting EGFR by inducing degraders is a promising approach towards improving therapeutic efficacy and augmenting the effect of nimotuzumab. Here we describe rational discovery of OTP-3, an oxidized (−)-Epigallocatechin gallate (EGCG) derivative that elicits potent anticancer activity in EGFR wild type NSCLC. Mechanistic studies disclosed that OTP-3 directly binds to EGFR extracellular domain decreases EGF and EGFR binding affinities by combination with nimotuzumab. Molecular docking studies revealed that OTP-3-EGFR is a very stable complex. Further analyses showed that nimotuzumab combined with OTP-3 resulted in significantly promoted EGFR degradation and repressed downstream survival pathways. Accordingly, OTP-3 combined with nimotuzumab significantly inhibits tumor growth through degrading EGFR in vivo. Thus, OTP-3 can also serve as an effective therapeutic agent in NSCLC where it can augment the effects of nimotuzumab, a valuable property for combination agents.

Tumor Immunology and Immunotherapy of Non-Small-Cell Lung Cancer.

Historically, non-small-cell lung cancer (NSCLC) has been regarded as a nonimmunogenic tumor; however, recent studies have shown that NSCLCs are among the most responsive cancers to monoclonal antibody immune checkpoint inhibitors (ICIs). ICIs have dramatically improved clinical outcomes for a subset of patients (∼20%) with locally advanced and metastatic NSCLC, and they have also demonstrated promise as neoadjuvant therapy for early-stage resectable disease. Nevertheless, the majority of patients with NSCLC are refractory to ICIs for reasons that are poorly understood. Thus, major questions are: how do we initially identify the patients most likely to derive significant clinical benefit from these therapies; how can we increase the number of patients benefiting; what are the mechanisms of primary and acquired resistance to immune-based therapies; are there additional immune checkpoints besides PD-1/PD-L1 and CTLA-4 that can be targeted to provide greater clinical benefit to patients; and how do we best combine ICI therapy with surgery, radiotherapy, chemotherapy, and targeted therapy? To answer these questions, we need to deploy the latest technologies to study tumors and their microenvironment and how they interact with components of the innate and adaptive immune systems. There is also a need for new preclinical model systems to investigate the molecular mechanisms of resistance to treatment and identify novel therapeutic targets. Recent advances in technology are beginning to shed new light on the immune landscape of NSCLC that may uncover biomarkers of response and maximize the clinical benefit of immune-based therapies. Identification of the mechanisms of resistance should lead to the identification of novel targets and the generation of new therapeutic strategies that improve outcomes for a greater number of patients. In the sections below, we discuss the results of studies examining the immune microenvironment in NSCLC, summarize the clinical experience with immunotherapy for NSCLC, and review candidate biomarkers of response to these agents in NSCLC.

Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer

Platinum-based chemotherapy remains the cornerstone of treatment for most people with non-small cell lung cancer (NSCLC), either as adjuvant therapy in combination with a second cytotoxic agent or in combination with immunotherapy. Resistance to therapy, either in the form of primary refractory disease or evolutionary resistance, remains a significant issue in the treatment of NSCLC. Hence, predictive biomarkers and novel combinational strategies are required to improve the effectiveness and durability of treatment response 6for people with NSCLC. The aim of this study was to identify novel biomarkers and/or druggable proteins from deregulated protein networks within non-oncogene driven disease that are involved in the cellular response to cisplatin. Following exposure of NSCLC cells to cisplatin, in vitro quantitative mass spectrometry was applied to identify altered protein response networks. A total of 65 proteins were significantly deregulated following cisplatin exposure. These proteins were assessed to determine if they are druggable targets using novel machine learning approaches and to identify whether these proteins might serve as prognosticators of platinum therapy. Our data demonstrate novel candidates and drug-like molecules warranting further investigation to improve response to platinum agents in NSCLC.

Melittin inhibited glycolysis and induced cell apoptosis in cisplatinresistant lung adenocarcinoma cells via TRIM8

Chemotherapy is widely used for non-small cell lung cancer (NSCLC) patients at a late stage; however, NSCLC patients often acquire resistance to chemotherapeutic drugs, thus limiting the therapy efficacy. Melittin, a major component of bee venom, possesses anti-tumor activity in various cancer cells. Here, we examined the effects of melittin on A549/DDP cisplatin-resistant lung adenocarcinoma cells and xenografts formed from this cell line and investigated the possible target of melittin. Treatment with melittin resulted in the induction of cell apoptosis, glycolysis inhibition, and reduction of phosphorylated AKT (p-AKT) in A549/DDP cells. We also identified that tripartite motif-containing 8 (TRIM8) was a potential target of melittin. Moreover, we found that TRIM8 mRNA expression was elevated in NSCLC specimens as compared to adjacent normal tissues (N = 25) and that patients with high expression of TRIM8 had a poor prognosis for lung adenocarcinoma. The knockdown of TRIM8 had a similar effect of melittin, while overexpression of TRIM8 reversed the effects of melittin in A549/DDP cells. More importantly, we revealed that melittin enhanced cisplatin sensitivity in A549/DDP cells and tumor growth in vivo using a xenograft model of A549/DDP cells. In conclusion, melittin appears to be a potential chemotherapy sensitization agent in NSCLC.

Abstract 561: Preclinical efficacy data for the anti-CEACAM5-DM4 ADC SAR408701 supports further development in lung and gastro-intestinal cancers

Abstract Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a cell-surface glycoprotein highly expressed in several tumor types including non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and gastric cancer (GC). SAR408701 is an antibody-drug conjugate (ADC) which consists of anti-CEACAM5 antibody conjugated to the maytansinoid DM4 cytotoxic agent, a highly potent tubulin inhibitor. SAR408701 was investigated in a First in Human trial (FIH) in patients with advanced solid tumors. During the early dose escalation phase, preliminary anti-tumor activity was observed with objective response reported in 3 patients with CRC and 1 patient with GC. In an interim analysis of an ongoing expansion cohort of patients with non-squamous NSCLC and with CEACAM5 expression in ≥ 50% of tumor cells, 25% overall response rate (ORR) (8/32 evaluable patients) and 37.5% (12 patients) stable disease were observed. In parallel to FIH trial, several preclinical studies were performed to support the clinical development of SAR408701 in NSCLC, CRC and GC. A single mouse trial (SMT) was carried out on a panel of 28 patent-derived xenografts (PDX) covering the top 3 indications. The SMT format employs a single mouse per PDX model and treatment arm and uses RECIST criteria as readout. Results showed an efficacy profile in the preclinical trial close to that obtained in clinic with an ORR of 10% in CRC, of 50% in lung cancers and of 37.5% in GC. The efficacy of SAR408701 is correlated with CEACAM5 expression in lung and gastric indications. To further assess the potential of SAR408701 in NSCLC, preclinical investigations have been done to determine if an ADC-DM4 could be beneficially combined with immune checkpoint inhibitors (ICIs). The capacity of DM4-treated tumor cells to immunize immune competent mice to the tumor was evaluated, indicating that DM4 can induce immunogenic cell death. This result supports the development of SAR408701 in combination with ICIs in NSCLC. The combination of SAR408701 with 4 different standard of care (SoC) therapies were tested in 2 CRC PDX models, one sensitive and one resistant to SAR408701 alone. Combinations of SAR408701 were evaluated with either FOLFOX regimen, FOLFIRI regimen, TAS-102 or cetuximab. All combinations resulted in significantly better antitumor activity than single agent arms in both resistant and sensitive PDXs without an increase in toxicity and showed a therapeutic synergy. These results suggest that SAR408701 can be advantageously combined with SoC in gastro-intestinal (GI) cancers. In summary, preclinical data show that SAR408701 displays a strong antitumor activity as a single agent in NSCLC and in combination with SOC in GI cancers, supporting further development in these indications. Furthermore, SAR408701 could be a potential good candidate to be combined with ICIs in NSCLC. Citation Format: Stephanie Decary, Olivier Lemaitre, Anne-Marie Lefebvre, Alexandra Ferrier, Marielle Chiron, Dmitri Wiederschain, Anne-Sophie Lacoste-Bourgeacq, Nathalie Le Bail, Sukhvinder Sidhu, Cecile Combeau, Mustapha Chadjaa, Celine Nicolazzi. Preclinical efficacy data for the anti-CEACAM5-DM4 ADC SAR408701 supports further development in lung and gastro-intestinal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 561.

Targeted Therapy for Non-Small Cell Lung Cancer

Treatment of progressive non-small cell lung cancer (NSCLC) has advanced remarkably, due in part to the development of targeted therapies. Several gene alterations, including EGFR, ALK, ROS1, and BRAF, play important roles in carcinogenesis. Therefore, many targeted agents focusing these gene alterations have been developed and proving their therapeutic efficacies in many clinical trials. Now we should test these gene mutations and should apply treatments individually and properly to ensure the maximal survival benefit of each patient. In this review, we summarize the target genes and respective therapeutic agents in NSCLC.

Rosmarinic acid reverses non-small cell lung cancer cisplatin resistance by activating the MAPK signaling pathway.

Cisplatin (DDP) is one of the first‐line chemotherapeutic agents for non‐small cell lung cancer (NSCLC). However, repeated use of cisplatin in clinical practice often induces chemoresistance. The aims of this study were to investigate whether rosmarinic acid (RA) could reverse multidrug resistance (MDR) in NSCLC and to explore the underlying mechanisms. Our data demonstrated that RA significantly inhibited NSCLC cell proliferation and cell colony formation in a dose‐dependent manner, induced G1 phase cell cycle arrest and apoptosis, and increased the sensitivity of cell lines resistant to DDP. Mechanistically, RA inhibited NSCLC cell growth, arrested cell cycle, and induced apoptosis by activating MAPK and inhibiting the expression of P‐gp and MDR1, which correspondingly enhanced p21 and p53 expression. We observed that the growth of xenograft tumors derived from NSCLC cell lines in nude mice was significantly inhibited by combination therapy. We demonstrate that RA is a potentially effective MDR reversal agent for NSCLC, based on downregulation of MDR1 mRNA expression and P‐gp. Together, these results emphasize the putative role of RA as a resistance reversal agent in NSCLC.

Long non-coding RNA TUG1 enhances chemosensitivity in non-small cell lung cancer by impairing microRNA-221-dependent PTEN inhibition.

Long non-coding RNA taurine up-regulated gene 1 (TUG1) emerges as new players in gene regulation in several cancers; however, its mechanism of action in non-small cell lung cancer (NSCLC) has not been well-studied. Herein, we determined expression pattern of TUG1 in NSCLC and further identified its effect on the chemosensitivity of NSCLC. Low expression of TUG1 was found in NSCLC tissues obtained from non-responders to platinum-based chemotherapy and reflected poor overall survival. TUG1 overexpression was shown to inhibit cell proliferation, migration, invasion, but facilitate apoptosis and autophagy in NSCLC cells resistant to cisplatin (DDP). Smaller size of tumor xenografts of DDP resistant NSCLC cells in the presence of TUG1 demonstrated enhancement of chemosensitivity by TUG1 in vivo. High expression of miR-221 and low expression of PTEN were determined in cancer tissues obtained from non-responders to platinum-based chemotherapy and reflected poor overall survival. TUG1 inhibited miR-221 that targeted PTEN, as evidenced by an elevated expression of PTEN in the presence of miR-221 or the absence of TUG1. Our present study reveals a model of enhancement of chemosensitivity that consists of TUG1, miR-221 and PTEN. Modulation of their levels may offer a new approach for improving anti-tumor efficacy for chemotherapeutic agents in NSCLC.

Consensus on the use of immune-related response criteria to evaluate the efficacy of immunotherapy in non-small cell lung cancer.

Many methods used to assess the effectiveness of immune checkpoint (programmed death-ligand 1 or cytotoxic T-lymphocyte-associated protein 4) inhibitors for non-small cell lung cancer (NSCLC) are insufficient, as the therapeutic benefit of these agents is often underestimated. Consequently, immune-related evaluation criteria have been developed to better reflect their efficacy. The aim of this consensus was to obtain the opinion of lung cancer experts on the adequacy of immune-response criteria for evaluating the efficacy of these treatments. Through two rounds of a modified Delphi consensus, 18 Spanish lung cancer experts participated in a 15-item questionnaire regarding the use of immunotherapies for NSCLC and the assessment criteria used to evaluate their effectiveness. Consensus was achieved on 80% of the items in the questionnaire. The panelists agreed that although the Response Evaluation Criteria in Solid Tumors (RECIST) are standard for the evaluation of solid tumors, immune-related response criteria would be useful for measuring the efficacy of immunotherapy. In addition, they considered that an overall survival (OS) rate at 2-5years is the most useful end point for assessing the benefit of immunotherapy, as clinical benefit may extend beyond the RECIST criteria-defined progression of disease. Although immune-related response criteria have been developed to better evaluate the efficacy of immunotherapy, their use has not been validated and is restricted to investigational applications. However, they may prove to be a useful tool for measuring the efficacy of immunotherapy agents in NSCLC, especially the OS rate at 2-5years.

Early shifts in immune cell subsets to predict response to immune checkpoint blockade in non-small cell lung cancer (NSCLC).

105 Background: The use of immune targeted agents for NSCLC has improved outcomes for patients (pts) with metastatic disease. Biomarkers such as the neutrophil-to-lymphocyte ratio (NLR) prior to therapy have been shown to predict outcomes however little is known about dynamic changes in immune subset composition during therapy. Methods: A single institution, retrospective review was performed of 88 NSCLC pts who received anti-PD1 therapy. NLR and relative lymphocyte count (RLC) were recorded at baseline, 4 weeks after treatment initiation, and at every subsequent computed tomography scan until time of progression. Endpoints included overall survival (OS) and durable clinical benefit (DCB), defined as stable disease or response at 6 months after therapy. Non parametric tests were used to compare NLR and RLC between responders and non-responders, cox-proportional hazards regression analysis was used for univariate associations with OS and Kaplan-Meier survival curves were compared by the log-rank test. Results: Our cohort comprised of 60 male pts with a median age of 63 years and a median OS of 38.5 months. Baseline NLR and RLC were not associated with response to therapy (Mann Whitney p=0.25 and p=0.23, respectively). We identified a statistically significant higher RLC and lower NLR at week 4 in pts with DCB (Mann Whitney p=0.001). Continuous NLR and RLC values at 4 weeks were statistically significantly correlated with OS (HR=1.008, 95% CI 1.001-1.015, p=0.03 and HR=0.939, 95% CI 0.9-0.98, p=0.004 respectively). Using median RLC at 4 weeks as a threshold, pts with high RLC at 4 weeks had significantly favorable survival (log-rank p<0.0001). Using the previously reported cut-off point of NLR=4, pts with NLR>4 had significantly worse OS (log-rank p<0.0001). For pts with acquired resistance to therapy, RLC increased early during treatment followed by a decrease at the time of progression. Conclusions: Our findings suggest early immune cell subset dynamics are associated with clinical outcomes for NSCLC pts treated with anti-PD1 therapy. Our observations reflect the differential immune repertoire shifts and if prospectively validated may be used to stratify pts receiving immune targeted agents.

Vicenin-2 acts as a radiosensitizer of the non-small cell lung cancer by lowering Akt expression.

Non-small cell lung cancer (NSCLC) has a very high rate of incidence and is resistant to chemo- and radiotherapy. Vicenin-2 (VCN-2) is a flavonoid obtained from Ocimum sanctum L. and it has been reported to have radioprotective, anticancer, and radiosensitizing properties. We have conducted this study to check the effect of VCN-2 on the cell viability and the effect on PTEN (Phosphatase and tensin homolog), PI3KCA (Phosphatidylinositol 4, 5-biphosphate 3-kinase catalytic subunit alpha isoform/PI3K 110α subunit), and Akt1 when VCN-2 was used alone and in combination with radiation in the NSCLC cell line NCI-H23 (H23). We have also checked the effect of VCN-2 on various pro- and anti-apoptotic genes and the ultra-morphological changes that occurred in the cells when VCN-2 is used alone and in combination with radiation. VCN-2 was able to lower cancer cell survival and phosphorylated Akt while promoting the expression of pro-apoptotic genes and down-regulating anti-apoptotic genes. We also observed the apoptosis-associated ultra-morphological changes in the VCN-2-treated cells. Our study have demonstrated that VCN-2 can be a potential chemotherapeutic and radiosensitizing agent in NSCLC. © 2018 BioFactors, 45(2):200-210, 2019.

Atezolizumab for the First-Line Treatment of Non-small Cell Lung Cancer (NSCLC): Current Status and Future Prospects.

Purpose: Atezolizumab is a programmed death ligand 1 (PDL-1) blocking antibody that was approved for metastatic non-small cell lung cancer (NSCLC) in patients with disease progression. Various studies have been initiated to explore the effectiveness of atezolizumab among different patient cohorts and disease statuses, including as first-line therapy. The purpose of this paper is to identify and summarize the trials that use atezolizumab as a first-line agent in chemotherapy-naïve patients with NSCLC.Methods: A database search was performed on Pubmed, Embase, and Wiley Cochrane Library—Central Register of Controlled Trials to identify clinical trials using atezolizumab as first-line therapy in NSCLC. Additionally, ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP) were searched to identify relevant clinical trials. Conference abstracts from the American Society of Clinical Oncology, the European Society for Medical Oncology, and the American Association for Cancer Research were hand-searched. Any trial in which atezolizumab was used as first-line therapy in chemotherapy-naive patients with NSCLC was included.Results: Fifteen studies were ultimately included, all of which are current and ongoing. Of the 15 studies, 5 have reported results. When given in the first-line setting, atezolizumab had higher rates of objective response, progression-free survival, and overall survival, compared to the second and third-line settings. Among the 15 studies, atezolizumab is used as monotherapy (n = 5), in combination with chemotherapy (n = 6), in combination with targeted therapy such as bevacizumab (n = 1), as neoadjuvant/adjuvant therapy (n = 3), in combination with stereotactic body radiation therapy (n = 1), and in combination with or following chemoradiation (n = 1).Conclusion: Available evidence shows promising safety and efficacy with the use of atezolizumab as first-line therapy in NSCLC. Atezolizumab is currently being studied in a variety of treatment settings. If clinical benefits are shown, atezolizumab may deem to be a useful first-line agent in NSCLC.

Abstract 4402: MiR-195 potentiates the efficacy of microtubule-targeting agents in non-small cell lung cancer

Abstract Introduction: microRNAs (miRNAs) are a family of small noncoding RNAs (18-24 nt) that post-transcriptionally repress gene expression by direct binding to the 3' untranslated regions (UTRs) of their targets. By targeting cancer-related genes, miRNAs have been shown not only to regulate cancer growth/progression, but also to modulate the response of cancer cells to chemotherapy. Such miRNAs are potential candidates for therapeutic intervention. Aiming to identify functional miRNAs in non-small cell lung cancer (NSCLC), we performed a high-throughput screen and found that miR-195 inhibits the growth of NSCLC cells and sensitizes them to microtubule-targeting agents (MTAs), a family of chemotherapeutic drugs widely used for NSCLC treatment. The function and mechanism of miR-195 in NSCLC were demonstrated both in vitro and in vivo. Results: We demonstrated that miR-195 synergizes with both a traditional MTA (paclitaxel) and a recently discovered one (eribulin) to repress the growth of NSCLC cells. Overexpression of miR-195 sensitizes NSCLC cells to paclitaxel and eribulin, while knockout of miR-195 confers resistance to paclitaxel and eribulin. Importantly, lung tumors with miR-195 overexpression are more sensitive to eribulin treatment than control tumors. Induced expression of miR-195 in lung tumors potentiates the efficacy of eribulin to repress tumor growth. Additionally, we showed that miR-195 directly targets CHEK1 to regulate the response of NSCLC cells to paclitaxel and eribulin. The direct and specific binding of miR-195 to the 3'UTR of CHEK1 was confirmed by luciferase reporter assay. Repression of CHEK1 using siRNAs and chemical inhibitor synergizes with paclitaxel and eribulin to repress the growth of NSCLC cells. Overexpression of CHEK1 contributes to the resistance to paclitaxel and eribulin in NSCLC cells. Analysis of TCGA data shows that CHEK1 is significantly upregulated in lung tumors compared to adjacent normal tissues and that its upregulation is associated with worse recurrence-free and overall survival. Conclusions: We report the identification of miR-195 as a sensitizer to microtubule-targeting agents in NSCLC, mediated by its repression of CHEK1. Mouse xenografts with induced or constitutive overexpression of miR-195 show that tumors with high miR-195 expression are more sensitive to drug treatment and that induction of miR-195 potentiates the efficacy of eribulin in repressing tumor growth. These results highlight the possible application of miR-195 expression as a biomarker to predict patient response to MTAs and the potential for delivery of miR-195 mimic as an adjuvant to chemotherapy. Citation Format: Xiaojie Yu, Yiqiang Zhang, Xiuye Ma, Alexander Pertsemlidis. MiR-195 potentiates the efficacy of microtubule-targeting agents in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4402.