Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer

Roper, Nitin; Velez, Moises J.; Chiappori, Alberto; Kim, Yoo Sun; Wei, Jun S.; Sindiri, Sivasish; Takahashi, Nobuyuki; Mulford, Deborah; Kumar, Suresh; Ylaya, Kris; Trindade, Christopher; Manukyan, Irena; Brown, Anna‐Leigh; Trepel, Jane B.; Lee, Jungmin; Hewitt, Stephen M.; Khan, Javed; Thomas, Anish

doi:10.1038/s41467-021-24164-y

Cited by 100 publications

(71 citation statements)

References 61 publications

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“…19 In addition, a recent study suggests that the Notch signalling is elevated in SCLC patients who are sensitive to ICIs, and could serve as a possible determinant of response to ICIs in SCLC patients. 28 Of note, the results from our analysis also showed that platinum-resistant patients could be significantly benefited from immunotherapy. Further exploration of potential predictive factors is needed.…”

Section: Discussionmentioning

confidence: 52%

The efficacy and safety of immune checkpoint inhibitor in patients with relapsed small‐cell lung cancer: A systematic review and meta‐analysis

Chen

Ding

et al. 2021

Clinical Pharmacy Therapeu

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What is Known and Objective Immune checkpoint inhibitors (ICIs) have been approved for treating small‐cell lung cancer (SCLC). However, the efficacy and safety profile of ICIs for relapsed SCLC remains under investigation. In this study, we assessed the efficacy and safety of ICIs in the treatment of relapsed SCLC patients. Methods The databases, including Pubmed, Embase, and the Cochrane library, were systematically searched to retrieve potential eligible studies from the establishment of the database to May 2021. The primary outcomes were survival, treatment responses, and safety. Randomized controlled trials and real‐world studies that met the inclusion criteria were included. The RevMan 5.4 and R software were used for meta‐analysis. Results and Discussion A total of eight articles involving 653 patients was included. Meta‐analyses results showed that the overall response rate (objective response rate [ORR]) of the ICIs group was 0.12 (95% confidence interval [CI]: 0.07–0.18). The median overall survival was 7.97 (95% CI: 5.94–9.47) months, while the progression‐free survival was 1.70 (95% CI: 1.40–2.28) months. Although chemotherapy showed a favourable ORR (odds ratio [OR] = 0.74; 95% CI: 0.39–1.41; p = 0.36) and a significantly better disease control rate (OR = 0.28; 95% CI: 0.11–0.70; p = 0.007), patients treated with ICIs had a reduced risk of mortality (hazard ratio = 0.87; 95% CI: 0.73–1.03; p = 0.10). With regards to adverse events (AEs), the rates of any AEs and ≥grade 3 AEs were 0.56 (95% CI: 0.52–0.60) and 0.13 (95%CI: 0.06–0.20), respectively. What is New and Conclusion For relapsed SCLC patients, the administration of ICIs resulted in a similar survival outcome and acceptable safety compared with chemotherapy. Further studies are needed to explore potential biomarkers for relapsed SCLC patients who may benefit from immunotherapy.

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Section: Discussionmentioning

confidence: 52%

The efficacy and safety of immune checkpoint inhibitor in patients with relapsed small‐cell lung cancer: A systematic review and meta‐analysis

Chen

Ding

et al. 2021

Clinical Pharmacy Therapeu

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“… 25 Nitin Roper et al disclosed that different transcriptional SCLC subtypes could experience clinical benefit to ICIs, as was Notch signaling activation, which might provide the means for more effective application of ICIs in SCLC. 26 Chemo-immunotherapy has become the preferred initial treatment for advanced SCLC, but only a small subset of SCLC patients’ benefits from ICIs, and there is an urgent need for biomarkers with efficient prediction. 27 …”

Section: Discussionmentioning

confidence: 99%

Genetic Alteration and Their Significance on Clinical Events in Small Cell Lung Cancer

Jiao

Zhang

Wang

et al. 2022

CMAR

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Introduction Small cell lung cancer (SCLC), an aggressive subtype of lung cancer characterized by the development of neuroendocrine tumors, is prone to distant metastasis, resistant to platinum-based drugs and has a poor prognosis. The development of next-generation sequencing technology (NGS) has led to the identification of many genetic alterations in SCLC. Few druggable targeted molecules can be used in clinical practice. Currently, NGS is widely employed in routine clinical practice of non-small cell lung cancer to assist in therapeutic options and prognosis evaluation. This study aims to investigate genes involved in small cell lung cancer (SCLC), their occurrence and their significance in clinical events. Methods Tumor tissue specimens from 18 Chinese SCLC patients were collected through a 520 cancer‐related genes panel for next-generation sequencing. First, the association between sequence results and clinical outcomes was examined. Subsequently, data on clinical pathology and sequencing results were analyzed. Results The Kaplan–Meier curve displayed a significant reduction in PFS for SCLC patients with LRP1B or MAP3K13 mutations. Overall survival (OS) of SCLC patients with MSH6 mutation was significantly higher than those with SPEN mutation. Conclusion Next-generation sequencing demonstrates that the genetic landscape of SCLC. Mutation status of LRP1B, MAP3K13, MSH6 and SPEN has prognostic significance, which might be potential therapeutic targets. We found possible genes and related signaling pathways that affect metastasis. These results can improve our understanding of the mutation characteristics of SCLC and identify potential biomarkers to guide targeted therapies.

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“…In addition, patients with low W_Score had high enrichment scores in the immune-related signaling pathways. Roper et al discovered that high expression of genes with antigen-processing machinery was beneficial for checkpoint immunotherapy (Roper et al, 2021). Ahn et al reported that the PD-1 blockade promoted the activation of CD8 + T effectors and resulted in faster clearance of infection (Ahn et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Crosstalk Between Four Types of RNA Modification Writers Characterizes the Tumor Immune Microenvironment Infiltration Patterns in Skin Cutaneous Melanoma

Zhang

Xiong

Zheng

et al. 2022

Front. Cell Dev. Biol.

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The “writers” of four types of adenosine (A)-related RNA modifications (N6-methyladenosine, N1-methyladenosine, alternative polyadenylation, as well as A-to-inosine RNA editing) are closely related to the tumorigenesis and progression of many cancer types, including skin cutaneous melanoma (SKCM). However, the potential roles of the crosstalk between these RNA modification “writers” in the tumor microenvironment (TME) remain unclear. The RNA modification patterns were identified using an unsupervised clustering method. Subsequently, based on differentially expressed genes responsible for the aforementioned RNA modification patterns, an RNA modification “writer” scoring model (W_Score) was constructed to quantify the RNA modification-associated subtypes in individual patients. Moreover, a correlation analysis for W_Score and the TME characteristics, clinical features, molecular subtypes, drug sensitivities, immune responses, and prognosis was performed. We identified three RNA modification patterns, corresponding to distinct tumor immune microenvironment characteristics and survival outcomes. Based on the W_Score score, which was extracted from the RNA modification-related signature genes, patients with SKCM were divided into high- and low-W_Score groups. The low-W_Score group was characterized by better survival outcomes and strengthened immunocyte infiltration. Further analysis showed that the low-W_Score group was positively associated with higher tumor mutation burden and PD-L1 expression. Of note, two immunotherapy cohorts demonstrated that patients with low W_Score exhibited long-term clinical benefits and an enhanced immune response. This study is the first to systematically analyze four types of A-related RNA modifications in SKCM, revealing that these “writers” essentially contribute to TME complexity and diversity. We quantitatively evaluated the RNA modification patterns in individual tumors, which could aid in developing personalized immunotherapy strategies for patients.

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Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer

Cited by 100 publications

References 61 publications

The efficacy and safety of immune checkpoint inhibitor in patients with relapsed small‐cell lung cancer: A systematic review and meta‐analysis

The efficacy and safety of immune checkpoint inhibitor in patients with relapsed small‐cell lung cancer: A systematic review and meta‐analysis

Genetic Alteration and Their Significance on Clinical Events in Small Cell Lung Cancer

Crosstalk Between Four Types of RNA Modification Writers Characterizes the Tumor Immune Microenvironment Infiltration Patterns in Skin Cutaneous Melanoma

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