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Reanalysing gene activity in small-cell lung cancer tumours found that the fourth kind is not defined by a control protein at all but by inflammation, and it is the one kind that clearly gains from adding immunotherapy.
Using tumour expression data and non-negative matrix factorisation, four subtypes of small-cell lung cancer were identified, defined largely by differential expression of the transcription factors ASCL1, NEUROD1 and POU2F3, or by low expression of all three signatures accompanied by an inflamed gene signature (SCLC-A, N, P and I respectively). SCLC-I experienced the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each had distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts induced intratumoral shifts towards SCLC-I, supporting subtype switching as a mechanism of acquired platinum resistance.
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.
Shares ASCL1, YAP1, Small cell lung cancer (KEGG map), DLL3.
Shares ASCL1, YAP1, Small cell lung cancer (KEGG map), DLL3.
Shares Cancer Cell, The cancer-immunity cycle, Hot vs cold tumours, PD-1 / PD-L1 immune checkpoint & T-cell activation.
Shares DLL3, RNA sequencing & expression profiling, Small-cell lung cancer, Non-small-cell lung cancer.
Shares The cancer-immunity cycle, Hot vs cold tumours, PD-1 / PD-L1 immune checkpoint & T-cell activation, Immune checkpoint inhibitors.
Shares The cancer-immunity cycle, PD-1 / PD-L1 immune checkpoint & T-cell activation, Small-cell lung cancer, Immune checkpoint inhibitors.
Shares Transcriptional machinery & addiction, Lineage plasticity & neuroendocrine transformation, Non-small-cell lung cancer.
Shares Hot vs cold tumours, MD Anderson Cancer Center, PD-1 / PD-L1 immune checkpoint & T-cell activation, Immune checkpoint inhibitors.