Decoding epigenetic subtypes, resistance mechanisms and vulnerabilities of small cell lung cancer (B05)

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R. Hänsel-Hertsch and his team will employ their newly developed technologies to characterize the epigenetic mechanisms driving transcription factor activation and subtype plasticity in acquired drug resistance in SCLC. In the first funding period, they found increased chromatin accessibility and occupancy of MYC, YAP1, H2A.Z, and decreased G-quadruplex secondary structure formation in chemo-resistant SCLC, which they will now seek to validate and corroborate by studying additional specimens from mice and patients at relapse using single-cell omics profiling. They will then test the hypothesis that these epigenetic alterations cause actionable vulnerabilities by genetic manipulation of newly identified transcription factor involvement. The team will further test, whether particular proteins associated with these epigenetic alterations are also amenable to therapeutic intervention using small molecules.