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

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

doi:10.1172/jci70259

Cited by 123 publications

(104 citation statements)

References 47 publications

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“…Similarly, upstream kinases such as MKK4 (also known as MAPKK4) that can also activate JNKs can induce dormancy in other systems 42,43 . This supports the hypothesis that the activation of stress signalling pathways 11,18,44–46 could induce a sustained state of quiescence linked to dormancy.…”

Section: Quiescence and Stress Tolerance Signallingsupporting

confidence: 86%

“…Furthermore, using in vitro three-dimensional (3D) modelling they showed that production of fibronectin and β1 integrin activated MLCK and stress fibre formation to maintain proliferation 82 . Others 83 reproduced the first studies 84,85 showing that FAK, SRC and β1 integrins are required to prevent dormancy onset 46,86 . Importantly, pharmacological inhibition of SRC alone induced the dormancy or slow cycling of breast cancer cells, while inhibition of both MEK1 and SRC caused apoptosis of DTCs 46 , suggesting that this pathway can be specifically targeted in DTCs in different niches (FIG.…”

Section: Microenvironmental Regulation Of Dormancymentioning

confidence: 85%

“…In addition, residual DTCs are genetically heterogeneous 9,65,66,133,150 and awakening dormant DTCs would expand the genetic, and probably epigenetic, repertoire of mechanisms that would allow systemic disease to resist therapy. In support of this, awakened dormant tumour cells seem to rapidly fuel tumour recurrence in experimental systems 18,46,151 . Thus, we argue against awakening dormant DTCs and instead support keeping them dormant or eradicating them while dormant as an alternative strategy.…”

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confidence: 88%

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Mechanisms of disseminated cancer cell dormancy: an awakening field

2014

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Metastases arise from residual disseminated tumour cells (DTCs). This can happen years after primary tumour treatment because residual tumour cells can enter dormancy and evade therapies. As the biology of minimal residual disease seems to diverge from that of proliferative lesions, understanding the underpinnings of this new cancer biology is key to prevent metastasis. Analysis of approximately 7 years of literature reveals a growing focus on tumour and normal stem cell quiescence, extracellular and stromal microenvironments, autophagy and epigenetics as mechanisms that dictate tumour cell dormancy. In this Review, we attempt to integrate this information and highlight both the weaknesses and the strengths in the field to provide a framework to understand and target this crucial step in cancer progression.

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Section: Quiescence and Stress Tolerance Signallingsupporting

confidence: 86%

Section: Microenvironmental Regulation Of Dormancymentioning

confidence: 85%

mentioning

confidence: 88%

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Mechanisms of disseminated cancer cell dormancy: an awakening field

2014

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“…As mentioned above, a number of studies have demonstrated that SRC, Raf, and VEGFR2 could be potential targets for the treatment of TNBC (13,18,34,35). The SRC/Raf inhibitor, SKLB646, indeed showed a nice selective inhibition of TNBC cell lines bearing an overexpression of SRC and mutant Raf, MD-MB-231, and MD-MB-435 (36,37).…”

Section: Discussionmentioning

confidence: 97%

Preclinical Evaluation of a Novel Orally Available SRC/Raf/VEGFR2 Inhibitor, SKLB646, in the Treatment of Triple-Negative Breast Cancer

Zheng

Zhang

Chen

et al. 2016

Molecular Cancer Therapeutics

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Triple-negative breast cancer (TNBC) is the most aggressive and deadly breast cancer subtype. To date, chemotherapy is the only systemic therapy and prognosis remains poor. Herein, we report the preclinical evaluation of SKLB646 in the treatment of TNBC; SKLB646 is a novel multiple kinase inhibitor developed by us recently. This compound potently inhibited SRC and VEGFR2 with IC 50 values of 0.002 mmol/L and 0.012 mmol/L, respectively. It also considerably inhibited B-Raf and C-Raf with IC 50 values of 0.022 and 0.019 mmol/L, respectively. It exhibited significant antiproliferation and antiviability activities against TNBC cell lines. Studies of mechanism of action indicated that SKLB646 inhibited the activation of SRC signaling and blocked the MAPK signaling through inhibiting the Raf kinases. Interestingly, SKLB646 dose dependently downregulated the expression of Fra1, a transcriptional factor that plays a critical role in the epithelial-to-mesenchymal transition. In addition, SKLB646 could inhibit HUVEC proliferation, migration, and invasion. It effectively blocked the formation of intersegmental vessels in zebrafish embryos and displayed considerable antiangiogenic effects in the tumorinduced neovascularization zebrafish model. In TNBC xenograft models, SKLB646 suppressed the tumor growth in a dosedependent manner. Moreover, SKLB646 could remarkably inhibit TNBC cell migration and invasion in vitro. Furthermore, in an experimental lung metastasis model, the overall survival time of groups treated with SKLB646 was much longer compared with the control-, dasatinib-, and paclitaxel-treated groups. In a preliminary pharmacokinetic study, SKLB646 showed good pharmacokinetic properties. Taken together, the preclinical data show that SKLB646 could be a promising lead compound for the treatment of TNBC.

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“…1) [44]. Similarly, in a BCa dormancy model Touny et al have shown p38 MAPK is inhibitory [45]. Furthermore, they determined that proto-oncogene tyrosine-protein kinase Src (Src) inhibition can block proliferation (Fig.…”

Section: Molecular and Cellular Mechanisms Of Pca Dormancymentioning

confidence: 99%

The biology and clinical implications of prostate cancer dormancy and metastasis

et al. 2015

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Disseminated tumor cells (DTC) are detected early in the disease process in prostate cancer (PCa) patients and can persist after radical prostatectomy. DTC can remain dormant in patients with no evidence of disease for a prolonged period of time only to recur 10 or more years later. Recent advances in single cell genomics and transcriptomics have provided much needed insight into DTC biology and cancer dormancy in patients. With the development of new in vitro and preclinical models, researchers recapitulate the clinical events in patients and therefore allow further elucidation of the molecular mechanisms underlying cancer dormancy and escape. In this review we explore novel ideas on the detection, heterogeneous transcriptomic profiles, molecular and cellular mechanisms of dormancy, and potential mechanisms underlying dormancy escape by DTC. As such there is hope that identifying and targeting novel dormancy-associated pathways in patients with residual disease will have significant clinical implications for the treatment of PCa patients in the future.

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

Cited by 123 publications

References 47 publications

Mechanisms of disseminated cancer cell dormancy: an awakening field

Mechanisms of disseminated cancer cell dormancy: an awakening field

Preclinical Evaluation of a Novel Orally Available SRC/Raf/VEGFR2 Inhibitor, SKLB646, in the Treatment of Triple-Negative Breast Cancer

The biology and clinical implications of prostate cancer dormancy and metastasis

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