Genes-first and phenotypes-first paths to treatment resistance in hematological malignancies

Despite the outstanding achievements of precision medicine in hematology, many targeted therapies eventually fail due to the emergence of resistance mechanisms. Traditionally, a genocentric approach has been adopted to uncover the molecular underpinnings of treatment resistance. This has contributed to identifying resistance gene mutations and designing novel therapeutic molecules with increased potency for the mutant target. However, over the last five years, additional non-genetic adaptations have become increasingly recognized as crucial promoters of treatment resistance. In parallel, emerging works in the field of evolutionary biology suggest that advantageous phenotypic traits appear most often due to cell-intrinsic phenotypic plasticity and can arise independently of gene mutations. In selected cases, single genetic abnormalities such as those involving TP53 can prime human cells for plasticity and facilitate phenotypic variability. In this narrative review, we retrace the resistance mechanisms to targeted therapies in the framework of these novel evolutionary concepts. We highlight the dichotomy between genes-first and phenotypes-first pathways of treatment adaptation, with the former being driven by traditional single-point mutations and the latter initiated by the phenotypic diversity and the high-level plasticity of cancer cells. Focusing on resistance mechanisms to kinase inhibitors and BH3 mimetics in leukemias and lymphomas, we describe how each drug can trigger both escape routes, which may even coexist within the tumor bulk of individual patients. Lastly, we provide a three-step translational perspective on how to counteract phenotypes-first resistance mechanisms, with the aim of prolonging disease control in hematological malignancies.