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Sequencing 110 small-cell lung cancers found that losing both copies of TP53 and RB1 is obligatory. That is a loss of two brakes, not a gain of a target, which is why the disease has been so hard to drug.
George, Lim, Jang and colleagues, with Thomas as senior author, sequenced the genomes of 110 small-cell lung cancers. Bi-allelic inactivation of TP53 and RB1 was present in nearly all of them, sometimes through complex genomic rearrangements; two tumours with wild-type RB1 showed chromothripsis producing cyclin D1 overexpression, an alternative route to the same deregulation.
The paper explains the therapeutic history of the disease. Small-cell lung cancer is defined by the loss of two tumour suppressors, and a loss cannot be inhibited, so forty years of kinase inhibitor development passed it by. The NOTCH finding, inactivating mutations in a quarter of tumours with Notch activation suppressing tumour growth in mouse models, is the one actionable lead the study produced, and it led to DLL3.
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.
One of the most cited trial reports Europe PMC returns for DLL3 in Small-cell lung cancer, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure.
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.
Shares Run small-cell lung cancer as one platform with shared controls and subtype stratification, Tarlatamab for patients with previously treated small-cell lung cancer, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Rare and paediatric cancers without markets and the tag lung-evidence.
Shares Driver mutation, Next-generation sequencing (NGS), Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Whole-exome & whole-genome sequencing and the tag lung-evidence.
Shares Driver mutation, Next-generation sequencing (NGS), Nature, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch and the tag lung-evidence.
Shares Driver mutation, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Whole-exome & whole-genome sequencing, Rare and paediatric cancers without markets and the tag lung-evidence.
Shares Next-generation sequencing (NGS), Nature, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Whole-exome & whole-genome sequencing and the tag lung-evidence.
Shares Driver mutation, Next-generation sequencing (NGS), Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Rare and paediatric cancers without markets and the tag lung-evidence.
Shares Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data, Next-generation sequencing (NGS), Lab models that fail to predict what happens in patients, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch and the tag lung-evidence.
Shares Driver mutation, Next-generation sequencing (NGS), Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, The undruggable drivers and the tag lung-evidence.