Genetic and non-genetic mechanisms of cancer therapy resistance

A significant clinical problem and unmet need in cancer therapy represents the fact that almost all cancer patients treated, develop resistance to current therapeutic drugs. Cancer therapy resistance is intimately linked to tumor heterogeneity, either preexisting or acquired. Resistance is characterized by transcriptomic and phenotypic changes in both tumor cells and their tumor microenvironment (TME) as well as growth of cells that tolerate the treatment. In this context, drug resistance could either be mediated by the outgrowth of preexisting-refractory tumor-cell subpopulations present in a heterogeneous tumor cell pool, or alternatively the consequence of acquired alterations in the neoplastic cells leading to the generation of resistant cells (Fig.1). Insights into genomic and transcriptomic data from tumor cells contributed partly to a mechanistic understanding of treatment failure. However, in over 35% of cases non-genetically determined resistance mechanisms were postulated.

Non-genetic mechanisms of drug resistance could either represent the outgrowth of preexisting-refractory tumor-cell subpopulations (persister-cells), which carry an epigenetic pattern mediating a resistant phenotype or alternatively resistance could be the consequence of acquired epigenetic, intra-tumor heterogeneity with the generation of resistant cells. The molecular pathways leading to non-genetic alteration driving cancer therapies are not understood. This is however, of upmost importance since an improved mechanistic understanding of therapy resistance could support the discovery of novel vulnerabilities providing directions for novel therapeutic avenues.

We will focus our work on acute myeloid leukemia (AML) and lung cancer.