Researchers reveal a new metabolic mechanism involved in resistance to lung cancer treatments

Lung cancer remains the leading cause of cancer-related death worldwide. In Spain, it causes over 22,000 deaths each year — equivalent to one death every twenty minutes. Its treatment continues to pose a major challenge due to the emergence of therapeutic resistance, which reduces drug efficacy and favours relapse.

The most common form, non-small cell lung cancer (NSCLC), accounts for around 85% of cases. In some of these tumours, mutations are detected in the EGFR gene, a molecular switch that drives the uncontrolled growth of cancer cells. This knowledge has led to the development of tyrosine kinase inhibitors (TKIs) — targeted drugs that block the abnormal activity of EGFR —, representing a major breakthrough in treatment by increasing survival and improving patients’ quality of life. However, over time, many tumours stop responding to TKIs or develop resistance mechanisms, reducing the effectiveness of these treatments and complicating the clinical management of the disease.

A metabolic shift that opens up new therapeutic avenues

The study, led by the Department of Physiology of the UV and the IIS La Fe, demonstrates that resistant tumour cells overproduce the enzyme NNMT, which is responsible for disrupting vitamin B3 metabolism. This alteration lowers the levels of a molecule essential for cell survival, NAD⁺, forcing the cells to depend on another enzyme, NAMPT, to continue proliferating.

“When we block NAMPT pharmacologically, the cells resistant to anti-EGFR therapy stop growing, both in cell cultures and in animal models”, explains Agustín Lahoz, researcher at IIS La Fe. “This allows us to identify a new Achilles heel that could be exploited through combination therapies to prevent relapse. However, its efficacy will need to be confirmed in clinical trials before it can be applied in medical practice”, he adds.

In addition, the team has discovered a non-invasive biomarker, the metabolite 1-MNA, whose elevated levels in blood are associated with poorer prognosis in patients treated with EGFR TKIs. Detectable through routine blood tests, this biomarker could help predict treatment response and monitor the emergence of resistance in real time, enabling more personalised clinical decisions. “This work shows that collaboration between basic and clinical researchers accelerates the transformation of laboratory findings into new diagnostic and therapeutic tools that extend patients’ lives and improve their quality of life”, concludes Julián Carretero, researcher at the Department of Physiology at the UV.

The project also involved clinical researchers from the INCLIVA Health Research Institute, the General University Hospital of Valencia and the Hospital de la Ribera.

Reference:

NNMT-driven metabolic reprogramming creates a NAMPT druggable vulnerability and reveals liquid biopsy biomarkers for TKI resistance in EGFR-mutant NSCLC. I. Pulido, J.C. García-Cañaveras, M.L. Rodríguez, J.H. Becker, A. López, M. Aupí, S. Aparisi, L. Chuliá-Peris, E. Tamayo-Torres, C. Carreres-Rey, J. Alcácer Fernández-Coronado, M. Benet, S. Montero, S. Mena, J. Sandoval, J. Pereda, J. Alcácer, S. Calabuig-Fariñas, E. Jantus-Lewintre, A. Cremades, J. Carretero, Cancer Letters. Advance online publication. https://doi.org/10.1016/j.canlet.2025.218032