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Negative Feedback and Adaptive Resistance to the Targeted Therapy of Cancer
Open accessAbstract
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. Sigificance: 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. Cancer Discov; 2(4): 311–9. ©2012 AACR.
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Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218 · cited 1×
“Oncogene-induced senescence is among the mechanisms that is thought serve as a safeguard against transformation (8).”
Carracedo, A., Ma, L., Teruya-Feldstein, J., Rojo, F., Salmena, L., Alimonti, A., Egia, A., Sasaki, A. T., Thomas, G., Kozma, S. C., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34739 · Cited by 1,381
AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity
Chandarlapaty, S., Sawai, A., Scaltriti, M., Rodrik-Outmezguine, V., Grbovic-Huezo, O., Serra, V., Majumder, P. K., Baselga, J., & Rosen, N. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.10.031 · Cited by 967
Self-citationCloughesy, T. F., Yoshimoto, K., Nghiemphu, P., Brown, K., Dang, J., Zhu, S., Hsueh, T., Chen, Y., Wang, W., Youngkin, D., et al. (2008) · PLoS Medicine · doi:10.1371/journal.pmed.0050008 · Cited by 593
A negative feedback signaling network underlies oncogene-induced senescence
Courtois-Cox, S., Genther Williams, S. M., Reczek, E. E., Johnson, B. W., McGillicuddy, L. T., Johannessen, C. M., Hollstein, P. E., MacCollin, M., & Cichowski, K. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.10.003 · Cited by 501
She, Q.-B., Halilovic, E., Ye, Q., Zhen, W., Shirasawa, S., Sasazuki, T., Solit, D. B., & Rosen, N. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.05.023 · Cited by 400 · cited 1×
“For instance, in tumors with RAS and PIK3CA mutations, downregulation of both AKT and ERK is necessary to fully recruit the 4EBP1 suppressor to the eIF4E mRNA cap complex to block cap-dependent translation (25).”
Ribes, V., & Briscoe, J. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a002014 · Cited by 232
Morrow, P. K., Wulf, G. M., Ensor, J., Booser, D. J., Moore, J. A., Flores, P. R., Xiong, Y., Zhang, S., Krop, I. E., Winer, E. P., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.32.2321 · Cited by 209
Research works printed but not linked: 22
- Alon, 2007, An Introduction to Systems Biology: Design Principles of Biological Circuits
- Ferrell, 2002, Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability, Curr Opin Cell Biol, 14, 140, 10.1016/S0955-0674(02)00314-9 · DOI · Paper page
- Avraham, 2011, Feedback regulation of EGFR signalling: decision making by early and delayed loops, Nat Rev, 12, 104, 10.1038/nrm3048 · DOI · Paper page
- Stelling, 2004, Robustness of cellular functions, Cell, 118, 675, 10.1016/j.cell.2004.09.008 · DOI · Paper page
- Bhalla, 2002, MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network, Science, 297, 1018, 10.1126/science.1068873 · DOI · Paper page
- Amit, 2007, A module of negative feedback regulators defines growth factor signaling, Nat Genet, 39, 503, 10.1038/ng1987 · DOI · Paper page
- Pratilas, 2009, (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway, Proc Natl Acad Sci U S A, 106, 4519, 10.1073/pnas.0900780106 · DOI · Paper page
- Poulikakos, 2010, RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF, Nature, 464, 427, 10.1038/nature08902 · DOI · Paper page
- Haruta, 2000, A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1, Mol Endocrinol, 14, 783, 10.1210/mend.14.6.0446 · DOI · Paper page
- O'Reilly, 2006, mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt, Cancer Res, 66, 1500, 10.1158/0008-5472.CAN-05-2925 · DOI · Paper page
- Shi, 2005, Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade, Mol Cancer Ther, 4, 1533, 10.1158/1535-7163.MCT-05-0068 · DOI · Paper page
- Tabernero, 2008, Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors, J Clin Oncol, 26, 1603, 10.1200/JCO.2007.14.5482 · DOI · Paper page
- Hsu, 2011, The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling, Science, 332, 1317, 10.1126/science.1199498 · DOI · Paper page
- Yu, 2011, Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling, Science, 332, 1322, 10.1126/science.1199484 · DOI · Paper page
- Vivanco, 2002, The phosphatidylinositol 3-Kinase AKT pathway in human cancer, Nat Rev Cancer, 2, 489, 10.1038/nrc839 · DOI · Paper page
- Alessi, 1996, Mechanism of activation of protein kinase B by insulin and IGF-1, EMBO J, 15, 6541, 10.1002/j.1460-2075.1996.tb01045.x · DOI · Paper page
- Rodrik-Outmezguine, 2011, mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling, Cancer Discov, 1, 248, 10.1158/2159-8290.CD-11-0085 · DOI · Paper page
- Serra, 2011, PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer, Oncogene, 30, 2547, 10.1038/onc.2010.626 · DOI · Paper page
- She, 2005, The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells, Cancer Cell, 8, 287, 10.1016/j.ccr.2005.09.006 · DOI · Paper page
- Carver, 2011, Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer, Cancer Cell, 19, 575, 10.1016/j.ccr.2011.04.008 · DOI · Paper page
- Sergina, 2007, Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3, Nature, 445, 437, 10.1038/nature05474 · DOI · Paper page
- Gajria, 2011, Combined inhibition of mTORC1 with temsirolimus and HER2 with neratinib: a phase I/II study in patients with metastatic HER2-amplified or triple-negative breast cancer, Cancer Res, 71
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The Achilles' heel of senescent cells: from transcriptome to senolytic drugs
Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., et al. (2015) · Aging Cell · doi:10.1111/acel.12344 · Cited by 2,584
“AKT is involved in regulating FOXO1 and mTOR, among other key pro-survival and metabolic homeostasis mechanisms (Chandarlapaty 2012).”
BackgroundTargeted drug delivery strategies for precision medicines
Manzari, M. T., Shamay, Y., Kiguchi, H., Rosen, N., Scaltriti, M., & Heller, D. A. (2021) · Nature Reviews Materials · doi:10.1038/s41578-020-00269-6 · Cited by 1,183
The PI3K/AKT/mTOR interactive pathway
Ersahin, T., Tuncbag, N., & Cetin-Atalay, R. (2015) · Molecular BioSystems · doi:10.1039/c5mb00101c · Cited by 683
Targeting cancer with kinase inhibitors
Gross, S., Rahal, R., Stransky, N., Lengauer, C., & Hoeflich, K. P. (2015) · Journal of Clinical Investigation · doi:10.1172/jci76094 · Cited by 444
Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer
Labrie, M., Brugge, J. S., Mills, G. B., & Zervantonakis, I. K. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00454-5 · Cited by 369
Metadata
- Authors
- Chandarlapaty, S.
- Venue
- Cancer Discovery
- Published
- 2012-04-01
- Volume
- 2
- Issue
- 4
- Pages
- 311-319
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2099516272
- Cited by
- 234
- References
- 8
- FWCI
- 5.92
- Type
- journal article
- Language
- en
- Open access
- green
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