Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

Stewart, C. Allison; Park, Elizabeth M.; Diao, Lixia; Groves, Sarah M.; Heeke, Simon; Nabet, Barzin Y.; Fujimoto, Junya; Solis, Luisa M.; Lü, Wei; Xi, Yuanxin; Cardnell, Robert J.; Wang, Qi; Fabbri, Giulia; Cargill, Kasey R.; Vokes, Natalie I.; Ramkumar, Kavya; Zhang, Bingnan; Corte, Carminia Maria Della; Robson, Paul; Swisher, Stephen G.; Roth, Jack A.; Glisson, Bonnie S.; Shames, David S.; Wistuba, Ignacio I.; Quaranta, Vito; Minna, John D.; Heymach, John V.; Byers, Lauren A.

doi:10.1016/j.ccell.2020.12.014

Cited by 481 publications

(759 citation statements)

References 64 publications

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“…Using tumor expression data and non-negative matrix factorization, Gay et al identified four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). Stating that the SCLC-I subgroup may benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2 [64]. Albeit uncommon, transformation of NSCLC into SCLC has been observed as a resistance mechanism upon treatment of EGFR-mutated NSCLC with EGFR tyrosine kinase inhibitors (TKI) (3% to 10% of EGFR-TKI resistant cases) [65,66].…”

Section: Genetic Variation Of Sclcmentioning

confidence: 99%

Pathology and Classification of SCLC

Raso

Bota-Rabassedas

Wistuba

2021

Cancers

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Lung cancer is consistently the leading cause of cancer-related death worldwide, and it ranks as the second most frequent type of new cancer cases diagnosed in the United States, both in males and females. One subtype of lung cancer, small cell lung carcinoma (SCLC), is an aggressive, poorly differentiated, and high-grade neuroendocrine carcinoma that accounts for 13% of all lung carcinomas. SCLC is the most frequent neuroendocrine lung tumor, and it is commonly presented as an advanced stage disease in heavy smokers. Due to its clinical presentation, it is typically diagnosed in small biopsies or cytology specimens, with routine immunostaining only. However, immunohistochemistry markers are extremely valuable in demonstrating neuroendocrine features of SCLC and supporting its differential diagnosis. The 2015 WHO classification grouped all pulmonary neuroendocrine carcinomas in one category and maintained the SCLC combined variant that was previously recognized. In this review, we explore multiple aspects of the pathologic features of this entity, as well as clinically relevant immunohistochemistry markers expression and its molecular characteristics. In addition, we will focus on characteristics of the tumor microenvironment, and the latest pathogenesis findings to better understand the new therapeutic options in the current era of personalized therapy.

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Section: Genetic Variation Of Sclcmentioning

confidence: 99%

Pathology and Classification of SCLC

Raso

Bota-Rabassedas

Wistuba

2021

Cancers

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“…As new therapeutic options are prospectively evaluated within the context of identified subtypes of SCLC, an increasing opportunity exists to further define predictive biomarkers. For example, POU2F3 expression may be as valuable in identifying tumors susceptible to PARP inhibition as SLFN11 expression [41,83]. The emerging "inflamed" subtype may also demonstrate improved responses to PARP inhibitors in combination with ICB [41,65,84], since preclinical data suggest that downstream DNA-sensing pathways remain intact in some tumors [70] and could amplify the effects of impaired DDR.…”

Section: Discussionmentioning

confidence: 99%

“…However, a subset of non-neuroendocrine tumors demonstrates enhanced inflammatory infiltrates and markers of innate immunity including restored STING expression [69,70]. As suggested by the phase II data for durvalumab + olaparib [65], and confirmed in elegant preclinical work [41], the non-neuroendocrine inflamed subtype may represent a biomarker for response to this combination. To expand the patient population that can benefit from the combination of DDR inhibition and ICB, novel approaches to restore tumor cell inflammatory pathways are sorely needed.…”

Section: Restoring Tumor Cell Inflammatory Signaling To Enhance Parp mentioning

confidence: 91%

“…SLFN11 expression is being studied prospectively as a biomarker in a randomized phase II clinical trial of talazoparib as maintenance therapy with atezolizumab in patients with ES-SCLC (SWOG1929, NCT04334941). Recent preclinical work argues that SCLC subtype can also influence response to PARP inhibitors, with expression of the transcription factor POU2F3 sensitizing to PARP inhibitors [41].…”

Section: Biomarkers Of Response To Parp Inhibitors In Sclcmentioning

confidence: 99%

“…The combination of EZH2 and PARP inhibitors was effective in preclinical models of ovarian cancer [73], and is being developed in SCLC, where both approaches have shown promise as monotherapies [21,74]. Restoring tumor suppressive NOTCH1 or inhibiting the Notch suppressive protein DLL3 to alter neuroendocrine differentiation could have similar effects, as recent evidence suggests that phenotype switching can uncover therapeutic vulnerabilities [41]. Targeting negative regulators of DNA-sensing including ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1), the enzyme that cleaves the STING second messenger 2′3′-cGAMP [75], may also potentiate the effects of DDR inhibition.…”

Section: Restoring Tumor Cell Inflammatory Signaling To Enhance Parp mentioning

confidence: 99%

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PARP Inhibitors in Small-Cell Lung Cancer: Rational Combinations to Improve Responses

Knelson

Patel

2021

Cancers

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Despite recent advances in first-line treatment for small-cell lung cancer (SCLC), durable responses remain rare. The DNA repair enzyme poly-(ADP)-ribose polymerase (PARP) was identified as a therapeutic target in SCLC using unbiased preclinical screens and confirmed in human and mouse models. Early trials of PARP inhibitors, either alone or in combination with chemotherapy, showed promising but limited responses, suggesting that selecting patient subsets and treatment combinations will prove critical to further clinical development. Expression of SLFN11 and other components of the DNA damage response (DDR) pathway appears to select for improved responses. Combining PARP inhibitors with agents that damage DNA and inhibit DDR appears particularly effective in preclinical and early trial data, as well as strategies that enhance antitumor immunity downstream of DNA damage. A robust understanding of the mechanisms of DDR in SCLC, which exhibits intrinsic replication stress, will improve selection of agents and predictive biomarkers. The most effective combinations will target multiple nodes in the DNA damage/DDR/immune activation cascade to minimize toxicity from synthetic lethality.

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Emerging Strategies for the Treatment of Small Cell Lung Cancer

Petty

Paz‐Ares

2023

JAMA Oncol

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ImportanceSmall cell lung cancer (SCLC) is an aggressive disease that is characterized by rapid growth and the early development of metastases. Patients typically respond to initial chemotherapy but quickly experience relapse, resulting in a poor long-term outcome. Therapeutic innovations that substantially improve survival have historically been limited, and reliable, predictive biomarkers are lacking.ObservationsThis review examines the biologic characteristics of SCLC, the current treatment landscape, and ongoing efforts to identify novel therapeutic targets. Ongoing research has advanced the understanding of molecular categories and the immunologic microenvironment of SCLC, which in turn has helped improve disease classification and staging. Recently, immunotherapy-based regimens have become available for the management of SCLC, with 2 programmed cell death 1 ligand 1 inhibitors approved in combination with chemotherapy for first-line treatment of extensive-stage disease. For second-line treatment, a novel alkylating agent, lurbinectedin, which inhibits oncogenic transcription, has been approved for use in patients with metastatic SCLC. Furthermore, a wide variety of therapies and innovative combination regimens are being continuously evaluated. Potential therapeutic strategies, including aurora kinase A inhibitors, polyadenosine diphosphate-ribose polymerase inhibitors, ataxia telangiectasia and Rad3-related inhibitors, cyclin-dependent kinase 7 inhibitors, delta-like protein 3 agents, antiganglioside agents, CD47 inhibitors, and lysine-specific histone demethylase 1a inhibitors, are also being examined.Conclusions and RelevanceTherapeutic optimization of SCLC remains a challenge, but recent trial results and drug approvals are encouraging. Advances in research have revealed critical information regarding biologic characteristics of the disease, which may lead to the identification of vulnerabilities and the development of new therapies. Further research focused on identifying biomarkers and evaluating innovative therapies will be paramount to improving treatment outcomes for patients with SCLC.

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Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

Cited by 481 publications

References 64 publications

Pathology and Classification of SCLC

Pathology and Classification of SCLC

PARP Inhibitors in Small-Cell Lung Cancer: Rational Combinations to Improve Responses

Emerging Strategies for the Treatment of Small Cell Lung Cancer

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