Journal: Cell discovery
This study analyzed 1,008 Chinese lung adenocarcinoma (LUAD) cases with paired whole-genome and transcriptome data, plus detailed longitudinal clinical and treatment information, to link molecular subtypes with therapy response.
Using transcriptomic features integrated with radiologic, pathologic, and microenvironmental characteristics, the authors defined four prognostically distinct LUAD subtypes:
- • LPI (low proliferation and invasion)
- • IMD (immune-desert)
- • IME (immune-enriched)
- • HPI (high proliferation and invasion)
Key therapeutic findings:
- • Tyrosine kinase inhibitors (TKIs) vs chemotherapy
- TKI therapy showed significantly better efficacy than chemotherapy in the LPI and IMD subtypes.
- In the HPI subtype, there was no clear efficacy difference between TKIs and chemotherapy.
- • Genomic determinants of TKI response
- VOPP1 amplification was associated with TKI resistance. Experimentally, VOPP1 knockdown restored TKI sensitivity.
- RRM2B amplification was associated with TKI sensitivity. RRM2B knockdown induced TKI resistance, whereas overexpression restored sensitivity.
- Patients with RRM2B amplification had an excellent outcome, with a 5-year survival rate approaching 100%.
- • Immunotherapy-relevant subtype
- The IME subtype showed high immune checkpoint activity and a higher frequency of DYNC2H1 mutation.
- Patients in the IME subtype benefited from immunotherapy, consistent with its immune-enriched profile.
Overall, the work proposes a clinically relevant LUAD classification that connects tumor biology, microenvironment status, and specific genomic alterations (e.g., VOPP1, RRM2B, DYNC2H1) to optimized use of TKIs, chemotherapy, and immunotherapy.