New Study Identifies Hidden Aggressive and Potentially Targetable Neuroendocrine-Like Subtype of Lung Cancer

A new study from researchers at Fox Chase Cancer Center and collaborators across multiple institutions has identified a hidden subset of lung cancers that behave more like aggressive neuroendocrine tumors than traditional non-small cell lung cancer (NSCLC).

By
June 3, 2026
4 min

Fox Chase Cancer Center

Objective:

To identify a previously underrecognized subset of lung cancers with aggressive neuroendocrine-like biology.

Approach:

Study Design: Analysis of DNA and RNA sequencing data from 49,144 lung cancer samples using the Caris Life Sciences database.
Transcriptomic Profiling: Development of a transcriptomic 'HGNEC activity score' to identify tumors with aggressive neuroendocrine-like biology.

Key Findings:

HGNEC-like tumors represent about 3-6% of NSCLC cases.
These tumors are associated with significantly shorter overall survival.
They are more likely to spread to lymph nodes and the brain.
HGNEC-like tumors are biologically aggressive and resemble small cell lung cancers.
They often lack PD-L1 expression, a marker for immunotherapy response.
High levels of neuroendocrine markers such as DLL-3 are present, which are targetable with specific therapies.
These tumors carry molecular alterations commonly associated with neuroendocrine cancers such as SCLC, including abnormalities in TP53 and RB1.

Interpretation:

The study suggests that advanced molecular testing could help identify high-risk tumors and personalize treatment strategies.

Limitations:

The study may not capture all biological differences due to reliance on existing pathology classifications.
The clinical significance of the findings needs further validation in larger cohorts.