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Curr Opin Genet Dev. 2017 Dec;47:41-47. doi: 10.1016/j.gde.2017.08.002. Epub 2017 Sep 9.

Natural diversity facilitates the discovery of conserved chemotherapeutic response mechanisms.

Author information

1
Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL 60208, USA; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA.
2
Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA. Electronic address: Erik.Andersen@Northwestern.edu.

Abstract

Organismal fitness depends on adaptation to complex niches where chemical compounds and pathogens are omnipresent. These stresses can lead to the fixation of alleles in both xenobiotic responses and proliferative signaling pathways that promote survival in these niches. However, both xenobiotic responses and proliferative pathways vary within and among species. For example, genetic differences can accumulate within populations because xenobiotic exposures are not constant and selection is variable. Additionally, neutral genetic variation can accumulate in conserved proliferative pathway genes because these systems are robust to genetic perturbations given their essential roles in normal cell-fate specification. For these reasons, sensitizing mutations or chemical perturbations can disrupt pathways and reveal cryptic variation. With this fundamental view of how organisms respond to cytotoxic compounds and cryptic variation in conserved signaling pathways, it is not surprising that human patients have highly variable responses to chemotherapeutic compounds. These different responses result in the low FDA-approval rates for chemotherapeutics and underscore the need for new approaches to understand these diseases and therapeutic interventions. Model organisms, especially the classic invertebrate systems of Caenorhabditis elegans and Drosophila melanogaster, can be used to combine studies of natural variation across populations with responses to both xenobiotic compounds and chemotherapeutics targeted to conserved proliferative signaling pathways.

PMID:
28892780
PMCID:
PMC5716832
[Available on 2018-12-01]
DOI:
10.1016/j.gde.2017.08.002
[Indexed for MEDLINE]
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