Functional Genomics Approaches to Elucidate Vulnerabilities of Intrinsic and Acquired Chemotherapy Resistance

Abstract

Drug resistance is a commonly unavoidable consequence of cancer treatment that results in therapy failure and disease relapse. Intrinsic (pre-existing) or acquired resistance mechanisms can be drug-specific or be applicable to multiple drugs, resulting in multidrug resistance. The presence of drug resistance is, however, tightly coupled to changes in cellular homeostasis, which can lead to resistance-coupled vulnerabilities. Unbiased gene perturbations through RNAi and CRISPR technologies are invaluable tools to establish genotype-to-phenotype relationships at the genome scale. Moreover, their application to cancer cell lines can uncover new vulnerabilities that are associated with resistance mechanisms. Here, we discuss targeted and unbiased RNAi and CRISPR efforts in the discovery of drug resistance mechanisms by focusing on first-in-line chemotherapy and their enforced vulnerabilities, and we present a view forward on which measures should be taken to accelerate their clinical translation.

RAD54L2 counters TOP2-DNA adducts to promote genome stability

“…In addition, in line with our finding that overexpression of RAD54L2 in WT cells generates etoposide resistance (Fig. 2D), high expression of RAD54L2 was recently associated with inferior event-free and overall survival of acute myeloid leukaemia (AML) patients in the AML02 cohort ( 33 – 35 ). As RAD54L2-mediated TOP2cc resolution could represent a mechanism for intrinsic or acquired tumor resistance to chemotherapies including TOP2 poisons, it represents a potential biomarker and a candidate target for anticancer drug discovery.…”

Differential effects of 5‐fluorouracil and oxaliplatin on autophagy in chemoresistant colorectal cancer cells

“…Multiple mechanisms can contribute to chemoresistance: drug efflux increasing molecule transporters; activation of alternative DNA repair pathways; oncogene activation or mutations in tumor suppressor genes; deregulation of apoptosis and metabolic reprogramming; overexpression of stem cell markers causing invasive phenotype; the existence of inherently resistant cell subpopulations; and elevated secretion of exosomes carrying resistance-promoting cargos and increased autophagic activity performing prosurvival functions. 1 Despite the fact that macroautophagy (hereafter autophagy) can both promote and inhibit cell death, there is mounting evidence that in the context of anticancer treatment it predominantly functions as a cell survival mechanism. 2 Therefore, silencing of key autophagy genes (e.g., ATG7) emerges as a potent strategy to reduce chemoresistance 3,4 Though the importance of autophagy in chemoresistance is established, the changes in autophagy in the case of acquired chemoresistance are poorly understood as well as the molecular targets for autophagy inhibition.…”

“…It may be pre‐existing (intrinsic) or acquired – newly developed after the drug treatment. Multiple mechanisms can contribute to chemoresistance: drug efflux increasing molecule transporters; activation of alternative DNA repair pathways; oncogene activation or mutations in tumor suppressor genes; deregulation of apoptosis and metabolic reprogramming; overexpression of stem cell markers causing invasive phenotype; the existence of inherently resistant cell subpopulations; and elevated secretion of exosomes carrying resistance‐promoting cargos and increased autophagic activity performing prosurvival functions 1 . Despite the fact that macroautophagy (hereafter autophagy) can both promote and inhibit cell death, there is mounting evidence that in the context of anticancer treatment it predominantly functions as a cell survival mechanism 2 .…”