Molecular Targets in Lung Cancer: Study of the Evolution of Biomarkers Associated with Treatment with Tyrosine Kinase Inhibitors—Has NF1 Tumor Suppressor a Key Role in Acquired Resistance?

SIMPLE SUMMARY: Resistance to tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer is crucial in the development of the disease. Detecting the mechanisms of this resistance is fundamental in lung cancer research, so we evaluated the presence of EGFR mutations in circulating free DNA in plasma of patients with NSCLC under oncological treatment. We studied the role of EGFR and other driver mutations in their involvement in acquired resistance to treatment with EGFR-TKIs and we analyzed the role of liquid biopsy as a non-invasive diagnostic method. Our results showed that liquid biopsy is a very useful tool monitoring the evolution of the disease and the resistance to TKIs. The detection of other concomitant mutations in driver genes is also key in this regard, so we found that alterations in the NFI tumor suppressor gene could be playing a role in disease progression and resistance to targeted therapies. ABSTRACT: The application to clinical practice of liquid biopsy in patients with lung cancer has led to an advance in the diagnosis and monitoring of the disease. Detection of alterations in EGFR genes related to TKI treatment in EGFR-mutated non-small cell lung cancer patients is a routine method in pathology laboratories. The primary objective of this work was to analyze the presence of EGFR mutations in cfDNA of 86 patients with lung cancer undergoing oncological treatment related to response to treatment with TKIs. Secondarily, we evaluated the dynamics of EGFR mutations, the presence of the T790M alteration and its relationship with drug resistance and analyzed by NGS molecular alterations in cfDNA of patients with discordant progression. Our results demonstrate that understanding the mutational status of patients treated with TKIs over time is essential to monitor disease progression. In this context, liquid biopsy is a fundamental key. In addition, it is not only necessary to detect EGFR mutations, but also other concomitant mutations that would be influencing the development of the disease. In this sense, we have discovered that mutations in the NF1 tumor suppressor gene could be exerting an as yet unknown function in lung cancer.