{"entity":{"id":"sclc-signalling","kind":"pathway","name":"Small cell lung cancer (KEGG map)","aka":["KEGG hsa05222","Small cell lung cancer"],"tldr":"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.\n\nWhat 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.","asOf":"2026-09-10","links":[{"label":"KEGG map hsa05222","url":"https://www.kegg.jp/pathway/hsa05222"},{"label":"Review: Small-cell lung cancer (Nat Rev Dis Primers 2021)","url":"https://doi.org/10.1038/s41572-020-00235-0"}],"tags":[],"related":["lineage-plasticity-neuroendocrine","p53-cell-cycle"],"cancers":["sclc","nsclc"],"sections":[],"technologies":[],"targets":["cdk4-6","tp53","akt","bcl2","rxr"],"drugs":["atezolizumab","durvalumab","serplulimab","tarlatamab","lurbinectedin","topotecan","ifinatamab-deruxtecan"],"companies":[],"institutions":[],"pathways":["p53-cell-cycle","cell-cycle-engine-cdks","apoptosis-bcl2","pi3k-akt-mtor","lineage-plasticity-neuroendocrine","transcription-addiction","pd1-checkpoint"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-rudin-nat-rev-dis-primers"],"journals":[],"dependsOn":[],"notes":[],"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.","nodes":[{"id":"myc","label":"MYC amplified","x":20,"y":6},{"id":"p27","label":"p15 / p27 (repressed)","x":50,"y":20},{"id":"cdk","label":"Cyclin D / CDK4/6, cyclin E / CDK2","x":20,"y":36,"targetId":"cdk4-6"},{"id":"rb1","label":"RB1 (lost)","x":20,"y":56},{"id":"e2f","label":"E2F, proliferation","x":20,"y":78},{"id":"p53","label":"TP53 (mutated)","x":55,"y":50,"targetId":"tp53"},{"id":"pten","label":"PTEN loss to PI3K / AKT","x":82,"y":20,"targetId":"akt"},{"id":"bcl2","label":"BCL2 / BCL-XL","x":82,"y":50,"targetId":"bcl2"},{"id":"apop","label":"Apoptosis","x":82,"y":78},{"id":"rxr","label":"RAR-beta / RXR (silenced)","x":55,"y":78,"targetId":"rxr"},{"id":"out","label":"Small cell lung cancer","x":50,"y":95}],"edges":[{"from":"myc","to":"p27","type":"inhibits"},{"from":"p27","to":"cdk","type":"inhibits"},{"from":"myc","to":"cdk","type":"activates"},{"from":"cdk","to":"rb1","type":"inhibits"},{"from":"rb1","to":"e2f","type":"inhibits"},{"from":"p53","to":"apop","type":"activates"},{"from":"p53","to":"cdk","type":"inhibits"},{"from":"pten","to":"apop","type":"inhibits"},{"from":"bcl2","to":"apop","type":"inhibits"},{"from":"e2f","to":"out","type":"activates"},{"from":"apop","to":"out","type":"inhibits"},{"from":"rxr","to":"out","type":"inhibits"}],"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"]},"route":"/pathways/sclc-signalling/","neighbours":{"pathway":[{"id":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","route":"/pathways/apoptosis-bcl2/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"cell-cycle-engine-cdks","kind":"pathway","name":"The cell-cycle engine (cyclins & CDKs)","route":"/pathways/cell-cycle-engine-cdks/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"}],"cancer":[{"id":"extensive-stage-sclc","kind":"cancer","name":"Extensive-stage small-cell lung cancer","route":"/cancers/extensive-stage-sclc/"},{"id":"limited-stage-sclc","kind":"cancer","name":"Limited-stage small-cell lung cancer","route":"/cancers/limited-stage-sclc/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"target":[{"id":"akt","kind":"target","name":"AKT","route":"/targets/akt/"},{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"cdk2","kind":"target","name":"CDK2","route":"/targets/cdk2/"},{"id":"cdk4-6","kind":"target","name":"CDK4/6","route":"/targets/cdk4-6/"},{"id":"cdkn2b","kind":"target","name":"CDKN2B","route":"/targets/cdkn2b/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"rxr","kind":"target","name":"Retinoid X receptor (RXR)","route":"/targets/rxr/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"atezolizumab","kind":"drug","name":"Atezolizumab","route":"/drugs/atezolizumab/"},{"id":"durvalumab","kind":"drug","name":"Durvalumab","route":"/drugs/durvalumab/"},{"id":"ifinatamab-deruxtecan","kind":"drug","name":"Ifinatamab deruxtecan","route":"/drugs/ifinatamab-deruxtecan/"},{"id":"lurbinectedin","kind":"drug","name":"Lurbinectedin","route":"/drugs/lurbinectedin/"},{"id":"serplulimab","kind":"drug","name":"Serplulimab","route":"/drugs/serplulimab/"},{"id":"tarlatamab","kind":"drug","name":"Tarlatamab","route":"/drugs/tarlatamab/"},{"id":"topotecan","kind":"drug","name":"Topotecan","route":"/drugs/topotecan/"}],"paper":[{"id":"paper-george-sclc-genomic-profiles-nature-2015","kind":"paper","name":"Comprehensive genomic profiles of small cell lung cancer","route":"/key-papers/paper-george-sclc-genomic-profiles-nature-2015/"},{"id":"paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","kind":"paper","name":"Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data","route":"/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/"},{"id":"paper-gay-sclc-subtypes-inflamed-cancer-cell-2021","kind":"paper","name":"Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities","route":"/key-papers/paper-gay-sclc-subtypes-inflamed-cancer-cell-2021/"},{"id":"paper-baine-sclc-subtype-immunohistochemistry-jto-2020","kind":"paper","name":"SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization","route":"/key-papers/paper-baine-sclc-subtype-immunohistochemistry-jto-2020/"},{"id":"paper-rudin-nat-rev-dis-primers","kind":"paper","name":"Small-cell lung cancer","route":"/key-papers/paper-rudin-nat-rev-dis-primers/"}]}}