Small-cell lung cancer transcription-factor subtypes (SCLC-A, SCLC-N, SCLC-P, SCLC-I) and SLFN11
Small-cell lung cancer has looked like one disease for fifty years; RNA profiling now splits it by the master transcription factor in charge (ASCL1, NEUROD1, POU2F3, or none with an inflamed signature), and these groups, plus the DNA-damage protein SLFN11, are the first leads for matching drugs to a cancer that has had almost no biomarkers.
Overview
What is measured: the dominant transcription factor and an immune signature. How: RNA expression or immunohistochemistry for ASCL1, NEUROD1 and POU2F3 on the biopsy (the original YAP1 group was replaced by the inflamed SCLC-I group by Gay and colleagues in 2021), SLFN11 by immunohistochemistry, DLL3 expression (high in SCLC-A), MYC amplification (SCLC-N); ctDNA methylation classifiers are in development because biopsies are small. Roughly: SCLC-A about half, DLL3-high and BCL2-high; SCLC-N about a quarter, MYC-driven with AURKA dependence; SCLC-P about a tenth, tuft-cell-like, sensitive to PARP inhibitors and nucleoside analogues; SCLC-I about 15 percent, with longer survival on atezolizumab in an exploratory IMpower133 analysis. SLFN11 expression predicts platinum and PARP inhibitor sensitivity (SWOG S1929 talazoparib maintenance). What a result changes: nothing yet in standard care, where everyone receives platinum-etoposide with a PD-L1 inhibitor; the subtypes select trial arms (tarlatamab against DLL3 is not subtype-restricted, ifinatamab deruxtecan against B7-H3, lurbinectedin, AURKA and BCL2 inhibitors) and are used to study transformation from EGFR-mutant adenocarcinoma. Where it matters: small-cell lung cancer, limited and extensive stage.
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