4.7 Article

Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation

期刊

JOURNAL OF HEMATOLOGY & ONCOLOGY
卷 14, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s13045-021-01186-z

关键词

Lineage plasticity; Squamous transdifferentiation; Treatment resistance; Targeted therapy

资金

  1. NCI [R01 CA197936, U24 CA213274]
  2. SU2C/VAI Epigenetics Dream Team
  3. Druckenmiller Center for Lung Cancer Research
  4. Parker Institute for Cancer Immunotherapy grant
  5. International Association for the Study of Lung Cancer grant
  6. NCI Cancer Center Support Grant (CCSG) [P30 CA08748]
  7. NIH [K08 CA-248723]
  8. Cycle for Survival
  9. Marie-Josee and Henry R. Kravis Center for Molecular Oncology
  10. NCI Cancer Center Support Grant [P30-CA008748 (R35 CA263816)]

向作者/读者索取更多资源

The study found that LUSC transdifferentiation in LUAD is primarily driven by transcriptional reprogramming rather than mutational events. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous-features in an EGFR-mutant patient-derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re-sensitized resistant squamous-like tumors to osimertinib. This provides potential therapeutic targets to constrain or prevent lineage plasticity.
Background Lineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transformation in the context of acquired resistance to targeted inhibition of driver mutations. LUAD-to-LUSC transdifferentiation, occurring in up to 9% of EGFR-mutant patients relapsed on osimertinib, is associated with notably poor prognosis. We hypothesized that multi-parameter profiling of the components of mixed histology (LUAD/LUSC) tumors could provide insight into factors licensing lineage plasticity between these histologies. Methods We performed genomic, epigenomics, transcriptomics and protein analyses of microdissected LUAD and LUSC components from mixed histology tumors, pre-/post-transformation tumors and reference non-transformed LUAD and LUSC samples. We validated our findings through genetic manipulation of preclinical models in vitro and in vivo and performed patient-derived xenograft (PDX) treatments to validate potential therapeutic targets in a LUAD PDX model acquiring LUSC features after osimertinib treatment. Results Our data suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events. We observed consistent relative upregulation of PI3K/AKT, MYC and PRC2 pathway genes. Concurrent activation of PI3K/AKT and MYC induced squamous features in EGFR-mutant LUAD preclinical models. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous-features in an EGFR-mutant patient-derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re-sensitized resistant squamous-like tumors to osimertinib. Conclusions Our findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and potential therapeutic targets to constrain or prevent lineage plasticity.

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