# Small cell lung cancer (KEGG map)

Source: https://onco.cc/pathways/sclc-signalling/  
OnCo record `sclc-signalling` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

KEGG's small cell lung cancer map shows a tumour with both master brakes removed, RB1 and TP53, plus amplified MYC pushing the cell cycle and PTEN loss and BCL2 keeping cells alive. Chemotherapy with PD-L1 antibodies and the DLL3 T-cell engager tarlatamab are the current answers.

## Summary

The KEGG small cell lung cancer map (hsa05222) describes a neuroendocrine tumour defined by loss of tumour suppressors rather than by a druggable activated kinase. RB1 loss or mutation removes the G1/S gate so E2F transcription runs freely; TP53 mutation removes DNA-damage-induced arrest and apoptosis (loss of p21, GADD45, BAX and BAK induction); PTEN loss releases PI3K to AKT survival signalling; and FHIT deletion on chromosome 3p removes a pro-apoptotic control. On the oncogene side, MYC family amplification (MYC, MYCL, MYCN) drives cyclin D and CDK4/6 and CDK2 while repressing the CDK inhibitors p15 (CDKN2B) and p27 (CDKN1B) through MAX and MIZ1. KEGG also draws BCL2 and BCL-XL overexpression that blocks the intrinsic apoptotic pathway, laminin and integrin signalling through FAK (PTK2) to PI3K and NF-kB, and retinoic acid signalling through RAR-beta and RXR, which is frequently silenced. Rudin et al., Nat Rev Dis Primers, 2021 (doi:10.1038/s41572-020-00235-0) review the near-universal RB1 and TP53 inactivation, the transcription-factor-defined subtypes (ASCL1, NEUROD1, POU2F3 and an inflamed subtype), and the therapeutic targets that follow, including DLL3, which is displayed on the surface of ASCL1-driven cells.

What drugs do about it: platinum and etoposide chemotherapy combined with a PD-L1 antibody (atezolizumab, durvalumab, or serplulimab against PD-1) is standard first-line treatment, with durvalumab also used after chemoradiotherapy in limited-stage disease. Tarlatamab, a DLL3 and CD3 bispecific T-cell engager, is approved for relapsed disease, and lurbinectedin or topotecan are second-line chemotherapy options. The B7-H3 antibody-drug conjugate ifinatamab deruxtecan is in late-stage trials.

## Fields

- Kind: Pathway
- Last checked: 2026-09-10
- Also known as: KEGG hsa05222; Small cell lung cancer
- Analogy: A train with both braking systems removed (RB1 and TP53) and a driver (MYC) shovelling coal. Nothing on the train can be switched off, so treatment works from outside: chemotherapy derails the fastest cars, and immunotherapy and tarlatamab summon T cells to attack a flag (DLL3) that the train happens to fly.
- Interventions: Platinum plus etoposide chemotherapy with a PD-L1 antibody (atezolizumab or durvalumab) or PD-1 antibody (serplulimab) for extensive-stage disease; durvalumab consolidation after chemoradiotherapy in limited-stage disease; DLL3 x CD3 bispecific T-cell engager tarlatamab for relapsed small cell lung cancer; Second-line chemotherapy: lurbinectedin or topotecan; B7-H3 antibody-drug conjugate ifinatamab deruxtecan in late-stage trials; Prophylactic or therapeutic cranial radiotherapy and thoracic radiotherapy in selected patients

## Sources

- KEGG map hsa05222: https://www.kegg.jp/pathway/hsa05222
- Review: Small-cell lung cancer (Nat Rev Dis Primers 2021): https://doi.org/10.1038/s41572-020-00235-0

## Connected records

- pathways: [Intrinsic apoptosis (BCL-2 family)](https://onco.cc/pathways/apoptosis-bcl2/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [The cell-cycle engine (cyclins & CDKs)](https://onco.cc/pathways/cell-cycle-engine-cdks/), [Transcriptional machinery & addiction](https://onco.cc/pathways/transcription-addiction/)
- cancers: [Extensive-stage small-cell lung cancer](https://onco.cc/cancers/extensive-stage-sclc/), [Limited-stage small-cell lung cancer](https://onco.cc/cancers/limited-stage-sclc/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/)
- targets: [AKT](https://onco.cc/targets/akt/), [BCL-2](https://onco.cc/targets/bcl2/), [CDK2](https://onco.cc/targets/cdk2/), [CDK4/6](https://onco.cc/targets/cdk4-6/), [CDKN2B](https://onco.cc/targets/cdkn2b/), [MYC](https://onco.cc/targets/myc-gene/), [RB1](https://onco.cc/targets/rb1/), [Retinoid X receptor (RXR)](https://onco.cc/targets/rxr/), [TP53](https://onco.cc/targets/tp53/)
- drugs: [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Durvalumab](https://onco.cc/drugs/durvalumab/), [Ifinatamab deruxtecan](https://onco.cc/drugs/ifinatamab-deruxtecan/), [Lurbinectedin](https://onco.cc/drugs/lurbinectedin/), [Serplulimab](https://onco.cc/drugs/serplulimab/), [Tarlatamab](https://onco.cc/drugs/tarlatamab/), [Topotecan](https://onco.cc/drugs/topotecan/)
- key papers: [Comprehensive genomic profiles of small cell lung cancer](https://onco.cc/key-papers/paper-george-sclc-genomic-profiles-nature-2015/), [Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data](https://onco.cc/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/), [Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities](https://onco.cc/key-papers/paper-gay-sclc-subtypes-inflamed-cancer-cell-2021/), [SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization](https://onco.cc/key-papers/paper-baine-sclc-subtype-immunohistochemistry-jto-2020/), [Small-cell lung cancer](https://onco.cc/key-papers/paper-rudin-nat-rev-dis-primers/)

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