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Unlike other epithelial cancer types, circulating tumor cells (CTCs) are less frequently detected in the peripheral blood of non-small cell lung cancer (NSCLC) patients using epithelial marker-based detection approaches despite the aggressive nature of NSCLC. Here, we demonstrate hexokinase-2 (HK2) as a metabolic function-associated marker for the detection of CTCs. In 59 NSCLC patients bearing cytokeratin-positive (CK pos ) primary tumors, HK2 enables resolving cytokeratin-negative (HK2 high /CK neg ) CTCs as a prevalent population in about half of the peripheral blood samples with positive CTC counts. However, HK2 high /CK neg tumor cells are a minority population in pleural effusions and cerebrospinal fluids. Single-cell analysis shows that HK2 high /CK neg CTCs exhibit smaller sizes but consistent copy number variation profiles compared with CK pos counterparts. Single-cell transcriptome profiling reveals that CK expression levels of CTCs are independent of their epithelial-to-mesenchymal transition (EMT) status, challenging the long-standing association between CK expression and EMT. HK2 high /CK neg CTCs display metastasis and EGFR inhibitor resistance-related molecular signatures and are selectively enriched in patients with EGFR   L858R  driver oncogene mutation as opposed to EGFR   19Del  , which is more frequently found in patients with prevalent CK pos CTCs in the blood. Consistently, treatment-naïve patients with a larger number or proportion of HK2 high /CK neg CTCs in the blood exhibit poor therapy response and shorter progression-free survival. Collectively, our approach resolves a more complete spectrum of CTCs in NSCLC that can potentially be exploited to identify patient prognosis before therapy.

Hexokinase 2 discerns a novel circulating tumor cell population associated with poor prognosis in lung cancer patients