Killing SCLC: insights into how to target a shapeshifting tumor

Sutherland, Kate D.; Ireland, Abbie S.; Oliver, Trudy G.

doi:10.1101/gad.349359.122

Cited by 36 publications

(26 citation statements)

References 175 publications

(339 reference statements)

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“…In the United States, small-cell lung cancer (SCLC) accounts for approximately 15% of all new lung cancer cases [1] where its incidence is on the decline due to decreased rates of cigarette smoking, which serves as the most established risk factor likely through a DNA damage-related mechanism [2]. By nature, and by predisposition, this highly aggressive neuroendocrine tumor doubles rapidly and disseminates widely early on, so that 80-85% of patients are diagnosed with advanced or extensive disease (ES-SCLC).…”

Section: Introductionmentioning

confidence: 99%

A 2022 Update on Extensive Stage Small-Cell Lung Cancer (SCLC)

Oronsky¹,

Abrouk²,

Caroen³

et al. 2022

J. Cancer

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For close to 40 years small-cell lung cancer (SCLC) was adrift, as listless, and as idle as a painted ship on a painted ocean, with nary a breeze to blow in the direction of clinical progress or change. The preferred decades-old first line regimen was etoposide-platinum, to which >50% of patients respond, followed by decades-old, tired topotecan in second line for platinum sensitive patients, full stop, because there were no approved therapeutic options (nor generally any compelling experimental ones) in third line or beyond. In 2012 SCLC was designated by the U.S. Congress as a "recalcitrant" tumor type and for good reason: because most patients relapse, after the generally favorable response in first line, respond poorly, if at all to subsequent therapies, and rarely survive beyond 1 year. A significant sea change occurred in 2018 with the approval of nivolumab followed by pembrolizumab and atezolizumab in 2019, durvalumab in 2020, accelerated approval for lurbinectedin in 2020 and trilaciclib in 2021 for myelosuppression. In 2021, the US indications for nivolumab and pembrolizumab were withdrawn. Suddenly, a tumor type, whose name was virtually synonymous with stalled progress and movement, and which was much less well studied and funded than its more prevalent cousin, non-small cell lung cancer (NSCLC), finds itself in the eye of the storm, that is, at the epicenter of an intense flurry and ferment of activity, not all of it positive. This review surveys approved drugs and select up-and-coming ones in development for extensive stage SCLC.

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Section: Introductionmentioning

confidence: 99%

A 2022 Update on Extensive Stage Small-Cell Lung Cancer (SCLC)

Oronsky¹,

Abrouk²,

Caroen³

et al. 2022

J. Cancer

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“… 17 These data and data from human tumors indicate that both inter- and intratumoral heterogeneity are likely key contributors of the ability of SCLC tumors to become resistant to therapies. 8 , 18 , 19 …”

Section: Introductionmentioning

confidence: 99%

DLL3 regulates Notch signaling in small cell lung cancer

Kim¹,

Ko²,

Sage³

2022

iScience

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“…The stratification of malignant cells within SCLC tumors into NE and non-NE cells and the increasing appreciation of the plasticity between these subtypes has led to increased interest in targeting this plasticity and the cooperation between NE and non-NE cells [7]. Activation of the YAP/Notch/REST network [5] has been implicated in NE to non-NE transdifferentiation in native pulmonary neuroendocrine cells (PNECs) in normal lung tissue (reference), SCLC [2,8,9], neuroblastoma (NBL) [10][11][12], and pan-cancer studies [13,14].…”

Section: Introductionmentioning

confidence: 99%

The small cell lung cancer neuroendocrine transdifferentiation explorer

Cai

Sondhi

Zhu

et al. 2022

Preprint

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SCLC is a high-grade neuroendocrine (NE) cancer that exhibits cellular plasticity. Transdifferention into non-NE cells creates considerable intra-tumoral heterogeneity, enhanced metastasis, greater tumor burden, and treatment resistance. Similar NE transdifferentiation has been observed in neuroblastoma (NBL). Targeting NE plasticity and cooperation between NE and non-NE cells in the tumor microenvironment may provide an avenue to enhance and restore sensitivity to available treatments. Although substantial transcriptomic changes take place upon NE transdifferentiation, conservation of these changes has not been investigated. In this study, we extensively curated genes associated with NE transdifferentiation in SCLC. We collected 35 datasets and compared the NE score-associated transcriptome across studies, for SCLC vs. NBL human tumors, human NBL tumors vs. cell lines, SCLC human tumors vs. tumors from genetically engineered mouse models (GEMMs), and SCLC GEMM uncultured cancer cells vs. cultured cancer cells. We have also created a user-friendly web application for researchers to explore these results. This work establishes a useful resource for researchers to understand the NE transdifferentiation landscape and explore context-dependent NE associations in SCLC and NBL.

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Killing SCLC: insights into how to target a shapeshifting tumor

Cited by 36 publications

References 175 publications

A 2022 Update on Extensive Stage Small-Cell Lung Cancer (SCLC)

A 2022 Update on Extensive Stage Small-Cell Lung Cancer (SCLC)

DLL3 regulates Notch signaling in small cell lung cancer

The small cell lung cancer neuroendocrine transdifferentiation explorer

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