In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 22_Supplement_1 ( 2015-11-15), p. A2-67-A2-67
Abstract:
Defects in cell-to-cell signaling pathways can result in developmental abnormalities as well as cancer. The Ras/MAPK pathway is a central regulator of gene expression, cellular proliferation, and differentiation that is frequently de-regulated in cancer. While this pathway is a promising target for cancer therapeutics, a major obstacle is the tendency of the pathway to become re-activated via feedback within hours following inhibition. This adaptive response is important because the timing and duration of Ras/MAPK activity are known to determine the resulting cellular response and gene expression pattern. We have developed a new live-cell reporter, EKAR3, that allows ERK activity to be monitored with high temporal precision and resolution of heterogeneous individual cell behavior. To track the detailed pattern of adaptation to Ras/MAPK pathway inhibitors, we imaged over 10,000 individual cells responding to specific inhibitors of EGFR, Raf, MEK, and ERK. ERK activity was immediately reduced upon inhibition, but returned after a period of time ranging from 1-12 hours, depending on the inhibitor and its concentration. Strikingly, different inhibitors were found to induce distinct ERK recovery patterns, ranging from frequent, high-amplitude pulses to extended steady-state activity. We then statistically analyzed the effect of these differential ERK responses on cell behavior to dissect elements of the temporal signal relevant for information transmission in the cell. Our results indicate that, at the level of individual cells, targeted inhibitors induce kinetically distinct adaptive responses, which are likely to determine their effectiveness in controlling different aspects of cellular proliferation, survival, and migration. Citation Format: Taryn E. Gillies, Kevin Distor, Marta Minguet Sànchez, Michael Pargett, John Albeck. Live cell imaging of ERK reveals unique inhibitor-specific adaptive responses. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-67.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.TRANSCAGEN-A2-67
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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