Targeting tumor resistance mechanisms

Abstract

Cancer develops resistance to treatments through many mechanisms. Single-cell analyses reveal the intratumor heterogeneity and dynamic relationships between cancer cell subpopulations. These analyses also highlight that various mechanisms of resistance may coexist in a given tumor. Studies have unraveled how the microenvironment affects tumor response to treatments and how cancer cells may adapt to these treatments. Though challenging, individualized treatment based on the molecular characterization of the tumor should become the new standard of care. In the meantime, the success rate of clinical trials in oncology remains dramatically low. There is a need to do better and improve the predictability of preclinical models. This requires innovative changes in ex vivo models and the culture system currently being used. An innovative ligand design is also urgently needed. The limited arsenal of medicinal chemistry reactions and the biases of scaffold selection favor structurally similar compounds with linear shapes at the expense of disc and spherical shapes, which leave a large chemical shape space untouched. In this regard, venoms have received increasing interest as a wellspring for drug candidates. Overall, the characterization of tumor heterogeneity has contributed to advancing our understanding of the mechanisms that underlie cancer resistance to treatments. Targeting these mechanisms will require setting key milestones to significantly improve the translatability of preclinical studies to the clinic with the hope of increasing the success rate of clinical trials.

Keywords: Therapeutic developments; organoids; translatability of preclinical studies; venoms.

Figure 1.. Blueprint of tumor resistance mechanisms.

A tumor is composed of genetically and epigenetically heterogeneous cell populations that interact with one another and with the microenvironment. Genetic alterations in signaling pathways that control cell proliferation, apoptosis, DNA repair, or expression of genes mediating treatment resistance are common hallmarks of cancer. These cells often display chromosomal instabilities and carry extrachromosomal DNA (ecDNA). These ecDNAs were shown to drive genetic heterogeneity, promote tumor aggressiveness, and lead to drug resistance. Epigenetic alterations drive cancer phenotype. Mutations have been identified in various classes of epigenetic modifiers involved in DNA methylation, chromatin remodeling, or histone post-translational modifications. Epigenetics also play a key role in the development of resistance mechanisms against anticancer treatments. Perturbations in lipid metabolism lead to alterations in the biophysical properties of the lipid bilayer. Furthermore, cancer cells often express a wide array of drug efflux transporters and uptake transporters, including ATP-binding cassette (ABC) transporters, non-ABC transporters, and solute carriers. Overall, these alterations have a major impact on drug uptake. There is a complex and dynamic interplay between the microenvironment and the tumor through continuous paracrine communication between tumoral and stromal cells. Hypoxia leads to the upregulation of many genes that mediate resistance to treatments, but it may dramatically impact the effectiveness of drugs depending on their redox properties. The acidic extracellular compartment also has important effects on the success of chemotherapy. Likewise, there is a continuous interaction between the tumor and the immune system. Although immunotherapy holds great promise, mechanisms of resistance have been identified, and these inevitably limit the clinical impact of this treatment strategy^,. Lastly, the microbiome has gained much attention over the past years. Studies have revealed that the gut microbiome may influence the outcome of immunotherapy^, or promote chemoresistance to colorectal cancer^,. Advances in the understanding of intratumor heterogeneity (ITH), the microenvironment, and their complex dynamic interplay will allow us to generate the blueprint of the mechanisms of cancer resistance to treatments.