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Combined SFK/MEK inhibition prevents metastatic outgrowth of dormant tumor cells
Lara H. El Touny, … , Mark J. Hoenerhoff, Jeffrey E. Green
Lara H. El Touny, … , Mark J. Hoenerhoff, Jeffrey E. Green
Published December 9, 2013
Citation Information: J Clin Invest. 2014;124(1):156-168. https://doi.org/10.1172/JCI70259.
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Research Article Oncology Article has an altmetric score of 16

Combined SFK/MEK inhibition prevents metastatic outgrowth of dormant tumor cells

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Abstract

Breast cancer (BC) can recur as metastatic disease many years after primary tumor removal, suggesting that disseminated tumor cells survive for extended periods in a dormant state that is refractory to conventional therapies. We have previously shown that altering the tumor microenvironment through fibrosis with collagen and fibronectin deposition can trigger tumor cells to switch from a dormant to a proliferative state. Here, we used an in vivo preclinical model and a 3D in vitro model of dormancy to evaluate the role of Src family kinase (SFK) in regulating this dormant-to-proliferative switch. We found that pharmacological inhibition of SFK signaling or Src knockdown results in the nuclear localization of cyclin-dependent kinase inhibitor p27 and prevents the proliferative outbreak of dormant BC cells and metastatic lesion formation; however, SFK inhibition did not kill dormant cells. Dormant cell proliferation also required ERK1/2 activation. Combination treatment of cells undergoing the dormant-to-proliferative switch with the Src inhibitor (AZD0530) and MEK1/2 inhibitor (AZD6244) induced apoptosis in a large fraction of the dormant cells and delayed metastatic outgrowth, neither of which was observed with either inhibitor alone. Thus, targeting Src prevents the proliferative response of dormant cells to external stimuli, but requires MEK1/2 inhibition to suppress their survival. These data indicate that treatments targeting Src in combination with MEK1/2 may prevent BC recurrence.

Authors

Lara H. El Touny, Anthony Vieira, Arnulfo Mendoza, Chand Khanna, Mark J. Hoenerhoff, Jeffrey E. Green

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Figure 2

SFK inhibition prevents the dormant-to-proliferative switch of D2.0R cells in fibrotic lungs but does not lead to regression of established lesions.

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SFK inhibition prevents the dormant-to-proliferative switch of D2.0R cel...
(A) Total lung surface burden of CD1nu/nu mice receiving Ad-empty (No fibrosis) or Ad–TGF-β223/225 (Fibrosis) and tail-vein injections of 1 × 106 D2.0R GFP cells, followed 24 hours later by 50 mg/kg body weight of AZD0530 daily for 21 days. (B) Lesions <1,000 pixels2 represent single dormant cells and lesions >1,000 pixels2 represent proliferative lesions. (C) Similar experiment as in A using 106 shNT D2.0R GFP or shSrc D2.0R GFP cells (clones 3 and 4). Lungs were evaluated 21 days after tail-vein injections. (D) Lesion distribution as determined in B. (E and F) Intervention experiment: experiment as in A, except gavage with 50 mg/kg body weight of AZD0530 was started 21 days after tail-vein injection of cells (schematic provided in E). (F) Lesion distribution determined as in B. No significant difference was detected between groups.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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