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Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for over 80% of all lung cancer cases. Despite the aggressive nature of NSCLC, circulating tumor cells that lead to metastasis are often not detected in the blood compared to breast, prostate, colorectal and other cancers.
Now, scientists have developed a new method to better detect circulating tumor cells (CTCs) which are a telltale sign of metastasis. The research was published in the journal Proceedings of the National Academy of Sciences (PNAS).
ISB and a collaborative team of researchers studied hexokinase-2, or HK2, a key enzyme in glucose metabolism. “A series of previous reports by our collaborator Dr Herschman (co-author of the article) and others have found that cancer cells often depend on HK2 to elevate glucose metabolism in order to fuel their uncontrolled growth, making this enzyme a desirable target for testing, “said BSI Assistant Professor Dr Wei Wei, lead correspondent author of the article.
Conventional methods of detecting CTC, as exemplified by the FDA-cleared CellSearch system, normally rely on the use of a family of proteins called cytokeratins (CKs) that are commonly found in epithelial tissue. Since about 90% of human cancers occur in epithelial tissue and express CKs, these methods work very well in many major types of cancer. However, their performance in NSCLC is sub-optimal, despite the very aggressive nature of NSCLC, which has been a long-standing headache in this area.
The researchers took up this challenge to achieve a broader spectrum for CTC detection by exploiting a common characteristic of a wide range of cancer cells – high glucose consumption due to high HK2 level. The use of HK2 as a biomarker allowed them to develop methods based on metabolic activity for the identification of a new population of CTC without CK expression which was normally neglected by conventional methods. This CTC CK-negative population was a prevalent subtype in 50 percent of the NSCLC patients analyzed and was the only subtype in a third of them, although all of these patients had CK-positive primary tumors, indicating that these tumor cells changed to CK-negative after detachment from the primary sites and rejection into the bloodstream in these patients with NSCLC.
The sequencing analysis revealed metastases and molecular signatures of drug resistance associated with CK negative for CK. Consistently, patients with CK-negative CTC in the blood exhibited a poorer therapeutic response, shorter progression-free survival, and a higher risk of metastasis. Interestingly, the researchers found that patients with the EGFRL858R mutation – a common NSCLC mutation treated with EGFR inhibitors – are more likely to have CK negative CTC circulating in their blood, which explains why part of a long-standing clinical observation, namely suboptimal therapy. Efficacy of first-line EGFR inhibitors in mutant EGFRL858R tumors.
“The use of HK2 as a tumor cell marker allows us to reveal a new population of circulating tumor cells which is not accessible with and is normally overlooked by current CTC detection methods based on epithelial markers,” said Wei. “In addition, this approach can be exploited to anticipate the therapeutic response of NSCLC patients before they undergo anticancer therapy, and more generally, it will be useful to identify CTCs from patients with a wide variety of cancers, independently. epithelial features. “
Reference: Yang L, Yan X, Chen J et al. Hexokinase 2 detects a new population of circulating tumor cells associated with a poor prognosis in patients with lung cancer. PNAS. 2021; 118 (11). doi: 10.1073 / pnas.2012228118
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