Small cell lung cancer (KEGG map)
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.
Overview
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.
In one picture
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.
Diagram
top- 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
Pages like this
not linked directly; found by shared links- TrialIDeate-Lung02
Shares Lurbinectedin, Topotecan, Ifinatamab deruxtecan, Small-cell lung cancer.
- TermLimited-stage vs extensive-stage (small-cell lung cancer)
Shares Serplulimab, Tarlatamab, Durvalumab, Atezolizumab.
- TrialATLANTIS
Shares Lurbinectedin, Topotecan, Small-cell lung cancer.
- PathwayAcute myeloid leukaemia (KEGG map)
Shares Retinoid X receptor (RXR), AKT, Intrinsic apoptosis (BCL-2 family), Transcriptional machinery & addiction.
- TermHallmark: evading growth suppressors
Shares The cell-cycle engine (cyclins & CDKs), AKT, CDK4/6, p53 / RB / cell-cycle checkpoint.
- PathwayMelanoma (KEGG map)
Shares The cell-cycle engine (cyclins & CDKs), AKT, CDK4/6, p53 / RB / cell-cycle checkpoint.
- PairingChemo-immunotherapy induction → maintenance intensification (SCLC)
Shares Lurbinectedin, Tarlatamab, Atezolizumab, Small-cell lung cancer.
- PathwayBladder cancer (KEGG map)
Shares The cell-cycle engine (cyclins & CDKs), CDK4/6, Durvalumab, Atezolizumab.