THE GENETIC BASIS OF RESISTANCE TO TARGETED THERAPY IN ONCOLOGY AND STRATEGIES FOR OVERCOMING IT

Abstract

The urgency of the problem is determined by the fact that targeted therapy has become one of the central directions of modern drug oncology, but its clinical effectiveness is limited by primary and acquired tumor resistance.

The genetic nature of this phenomenon is particularly significant for Russian practice, where the expansion of molecular testing is already influencing the choice of treatment for non-small cell lung cancer, melanoma, colorectal cancer, thyroid cancer, renal cell carcinoma and hepatocellular carcinoma. In case of resistance to tyrosine kinase inhibitors, anti-EGFR drugs, BRAF/MEK inhibitors, multikinase inhibitors, and drugs acting on the PI3K-AKT-mTOR cascade, secondary mutations of the therapeutic target, amplification of alternative receptors, reactivation of downstream signaling pathways, loss of suppressor genes, clonal selection, and spatial heterogeneity play a crucial role. tumors.

The practical significance of the topic is related to the fact that later identification of the molecular mechanism of progression leads to an empirical change in therapy lines, while repeated testing of tumor tissue and circulating tumor DNA allows choosing a more targeted strategy.

The article systematizes the genetic mechanisms of drug resistance and discusses strategies for overcoming it in Russian real-world clinical practice: preliminary stratification of patients, repeated molecular testing in case of progression, next-generation therapy, reintroduction of the anti-EGFR approach in molecularly selected patients, combined blockade of signaling cascades and redirection of radioiodresistant tumors.