Negative Feedback and Adaptive Resistance to the Targeted Therapy of Cancer

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Cancer Discovery (Impact Factor: 19.45). 04/2012; 2(4):311-9. DOI: 10.1158/2159-8290.CD-12-0018
Source: PubMed


Mutational activation of growth factor signaling pathways is commonly observed and often necessary for oncogenic transformation. Under physiologic conditions, these pathways are subject to tight regulation through negative feedback, which limits the extent and duration of signaling events after physiologic stimulation. Until recently, the role of these negative feedback pathways in oncogene-driven cancers has been poorly understood. In this review, I discuss the evidence for the existence and relevance of negative feedback pathways within oncogenic signaling networks, the selective advantages such feedback pathways may confer, and the effects such feedback might have on therapies aimed at inhibiting oncogenic signaling. SIGNIFICANCE: Negative feedback pathways are ubiquitous features of growth factor signaling networks. Because growth factor signaling networks play essential roles in the majority of cancers, their therapeutic targeting has become a major emphasis of clinical oncology. Drugs targeting these networks are predicted to inhibit the pathway but also to relieve the negative feedback. This loss of negative feedback can itself promote oncogenic signals and cancer cell survival. Drug-induced relief of feedback may be viewed as one of the major consequences of targeted therapy and a key contributor to therapeutic resistance.

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    • "Silencing EFNB3 expression down-regulates AKT in cancer cells (Stahl et al. 2013). AKT is involved in regulating FOXO1 and mTOR, among other key pro-survival and metabolic homeostasis mechanisms (Chandarlapaty 2012). PI3K is upstream of AKT and the PI3KCD (catalytic subunit δ) is specifically implicated in the resistance of cancer cells to apoptosis. "

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    • "Under physiological conditions, these inhibitory circuits fine-tune the level of signalling in response to growth factors, providing an appropriate response to external stimuli. Interestingly, persistence of negative feedback is found in tumour cells and seems to represent a major selection pressure for mutations in modulators of these feedback programmes (Chandarlapaty, 2012). Furthermore, persistent feedback inhibition provides an explanation of oncogene addiction as hyperdependency on the oncoprotein to sustain a certain strength of pathway output that acts to counter intrinsic inhibition (Pratilas et al, 2009; Chandarlapaty, 2012). "
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    • "In addition to the co-regulation of apoptotic proteins mentioned above, PI3K can also trigger ERK signaling pathways by activating RAS [53]. These signal pathways are regulated by various positive and negative crosstalk and feedback loops [54], [55]. It was illustrated that there might be interactions between these signaling pathways in GSCs, which needs to be further investigated. "
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