Inhibition of Karyopherin β1-mediated nuclear import of lineage-defining TFs in small cell lung cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA767882 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16155700.fastq.gz | Fastqsanger.gz | |||
| SRR16155701.fastq.gz | Fastqsanger.gz | |||
| SRR16155702.fastq.gz | Fastqsanger.gz | |||
| SRR16155703.fastq.gz | Fastqsanger.gz | |||
| SRR16155704.fastq.gz | Fastqsanger.gz |
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Project description:Extensive genomic studies support the classification of small cell lung cancer (SCLC) into subtypes based on expression of lineage-defining transcription factors including ASCL1 and NEUROD1, which together account for ~80% of this disease. ASCL1 and NEUROD1 activate SCLC oncogene expression and drive distinct transcriptional programs. ASCL1 is also required for tumorigenesis in SCLC mouse models, and both ASCL1 and NEUROD1 maintain the in vitro growth and oncogenic properties of ASCL1+ or NEUROD1+ SCLC cell lines. Strategies to inhibit ASCL1 and NEUROD1 may therefore represent an attractive, targeted SCLC therapy and provide a tool to investigate the underlying plasticity of the predominant SCLC subtypes. However, ASCL1 and NEUROD1 have long been considered “undruggable” vulnerabilities. Here, we use a proteomic approach to identify Karyopherin β1 (KPNB1) as a nuclear import receptor for ASCL1 and NEUROD1 in SCLC, and demonstrate that the inhibition of KPNB1 using a variety of genetic or pharmacological approaches leads to impaired ASCL1 and NEUROD1 nuclear accumulation and transcriptional activity. Pharmacological targeting of KPNB1 preferentially disrupts ASCL1/NEUROD1+ SCLC cell line growth in vitro and ASCL1+ tumor growth in an in vivo patient derived xenograft (PDX) model of SCLC.
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Project description:Genomic studies support the classification of small cell lung cancer (SCLC) into subtypes based on the expression of lineage-defining transcription factors ASCL1 and NEUROD1, which together are expressed in ∼86% of SCLC. ASCL1 and NEUROD1 activate SCLC oncogene expression, drive distinct transcriptional programs, and maintain the in vitro growth and oncogenic properties of ASCL1 or NEUROD1-expressing SCLC. ASCL1 is also required for tumor formation in SCLC mouse models. A strategy to inhibit the activity of these oncogenic drivers may therefore provide both a targeted therapy for the predominant SCLC subtypes and a tool to investigate the underlying lineage plasticity of established SCLC tumors. However, there are no known agents that inhibit ASCL1 or NEUROD1 function. In this study, we identify a novel strategy to pharmacologically target ASCL1 and NEUROD1 activity in SCLC by exploiting the nuclear localization required for the function of these transcription factors. Karyopherin β1 (KPNB1) was identified as a nuclear import receptor for both ASCL1 and NEUROD1 in SCLC, and inhibition of KPNB1 led to impaired ASCL1 and NEUROD1 nuclear accumulation and transcriptional activity. Pharmacologic targeting of KPNB1 preferentially disrupted the growth of ASCL1+ and NEUROD1+ SCLC cells in vitro and suppressed ASCL1+ tumor growth in vivo, an effect mediated by a combination of impaired ASCL1 downstream target expression, cell-cycle activity, and proteostasis. These findings broaden the support for targeting nuclear transport as an anticancer therapeutic strategy and have implications for targeting lineage-transcription factors in tumors beyond SCLC. The identification of KPNB1 as a nuclear import receptor for lineage-defining transcription factors in SCLC reveals a viable therapeutic strategy for cancer treatment.
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