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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.
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.
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.
It offers the first credible explanation for why only a minority of small-cell patients get a durable benefit from checkpoint blockade, and it introduces subtype switching, which would mean retesting at relapse rather than typing once.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
It is the reality check on the subtype model and it has a direct consequence for treatment: the DLL3-directed medicines are aimed at the neuroendocrine-high subtypes, and the POU2F3 and double-negative tumours will not express the target.
The organising framework for every small-cell lung cancer trial designed since. It is also why the slow progress in the disease is now attributed to treating four diseases as one rather than to the biology being intractable.
Why small-cell lung cancer has no targeted therapy in the conventional sense: it is built from the loss of TP53 and RB1, and the drugs that transformed non-small-cell disease inhibit gains rather than restore losses. The NOTCH result pointed at DLL3 and, eventually, at tarlatamab.
Shares Lurbinectedin, Ifinatamab deruxtecan, Tarlatamab, Limited-stage small-cell lung cancer.
Shares SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization, Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities, Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data, Transcriptional machinery & addiction.
Shares SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization, Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data, Tarlatamab, Limited-stage small-cell lung cancer.
Shares SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization, Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities, Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data, Lineage plasticity & neuroendocrine transformation.
Shares Tarlatamab, Serplulimab, Limited-stage small-cell lung cancer, Extensive-stage small-cell lung cancer.
Shares Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data, Comprehensive genomic profiles of small cell lung cancer, RB1, Limited-stage small-cell lung cancer.
Shares The cell-cycle engine (cyclins & CDKs), RB1, MYC, CDK4/6.
Shares SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization, Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data, Tarlatamab, Extensive-stage small-cell lung cancer.