Role and targeting of anaplastic lymphoma kinase in cancer

Viscardi, Giuseppe; Liello, Raimondo Di; Fasano, Morena; Martinelli, Erika; Troiani, Teresa; Ciardiello, Fortunato; Corte, Carminia M. Della

doi:10.1186/s12943-018-0776-2

Cited by 75 publications

(64 citation statements)

References 73 publications

(78 reference statements)

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“…Abnormal activation of ALK signaling through gene rearrangement, amplification, mutation or protein overexpression has been found in various human cancers, including neuroblastoma, glioblastoma, lung cancer, rhabdomyosarcoma, ovarian cancer, melanoma, colorectal carcinoma, astrocytoma, Ewing's sarcoma and retinoblastoma [4][5][6][7]. It is controversial whether alterations of ALK gene exist in BC.…”

Section: Discussionmentioning

confidence: 99%

“…ALK activates multiple pathways, including phospholipase C γ (PLCγ), Janus kinase -signal transducer and activator of transcription 3 (JAK/STAT3), Phosphoinositide 3-kinase-AKT (PI3K/AKT), mitogenactivated protein kinase (MAPK), sonic hedgehog, JUNB and RAPGEF1/RAP1 GTPase signaling cascades [7]. Aberrant activation of some of these pathways, such as JAK/STAT3, PI3K/AKT and sonic hedgehog, has been found to promote tumor metastasis and be associated with cell de-differentiation in BC [21][22][23].…”

Section: Discussionmentioning

confidence: 99%

“…and mesenchymal neoplasms such as anaplastic large cell lymphoma, lung cancer, inflammatory myofibroblastic tumors and neuroblastoma [4][5][6][7]. The role of ALK signaling in the pathogenesis of BC is not clear.…”

mentioning

confidence: 99%

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An Anaplastic Lymphoma Kinase Pathway Signature is associated with Cell De-differentiation, Neoadjuvant Response and Recurrence Risk in Breast Cancer

Liu

2019

Preprint

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The role of ALK signaling in the pathogenesis of breast cancer (BC) is not clear. Previously we generated a gene signature for ALK pathway based on the difference of gene expression profiles between tumor cells with activated and inactive ALK pathway. Here, this signature was used to compute ALK pathway activity in BC samples from 42 microarray datasets, and the associations between ALK pathway score and the clinical outcome were examined by logistic regression and survival analysis. Our results indicated that high ALK pathway activity was a significant risk factor for the presence of higher-grade breast cancer with loss of ER and PR expression in the 42 datasets (n= 6381). ALK pathway activity was also positively associated with pathological complete response (pCR) in 15 datasets annotated with patient’s neoadjuvant response information (n= 2093, overall OR 1.67, p=2.00E-12), and with recurrence risk in 30 datasets annotated with patient’s survival information (n= 4678, overall HR 1.21, p=3.31E-08). The associations of ALK pathway activity with pCR and recurrence were more significant in HER2 negative and grade 1&2 tumors than in HER2 positive and grade 3 tumors. Notably, the association between ALK and tumor recurrence was statistically significant in patient with age>50 but not ≤50 years old, in patient with positive but not negative lymph node and in patients with residual disease but not pCR following neoadjuvant chemotherapy. These data indicate that ALK may be involved in BC tumorigenesis and ALK pathway signature represents a novel biomarker for BC clinical management.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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An Anaplastic Lymphoma Kinase Pathway Signature is associated with Cell De-differentiation, Neoadjuvant Response and Recurrence Risk in Breast Cancer

Liu

2019

Preprint

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“…Several candidates of LATS regulators identified by our screen were already described in the literature (i.e., inhibitors of EGFR and PI3K) (18), whereas others [e.g., inhibitors of ALK, TBK1, and Janus kinase 2 (JAK2)] are novel. Among these candidate Hippo regulators identified, because ALK is a RTK that plays important roles in various biologic and pathologic processes (19)(20)(21), we further validated and characterized RTK ALK as a novel regulator of the Hippo pathway.…”

Section: Kinome-wide Kinase Inhibitor Screen Using the Lats-nbit-bsmentioning

confidence: 99%

A kinome‐wide screen using a NanoLuc LATS luminescent biosensor identifies ALK as a novel regulator of the Hippo pathway in tumorigenesis and immune evasion

Nouri

Azad²,

Lightbody³

et al. 2019

FASEB j.

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The Hippo pathway is an emerging signaling pathway that plays important roles in organ size control, tissue homeostasis, tumorigenesis, metastasis, drug resistance, and immune response. Although many regulators of the Hippo pathway have been reported, the extracellular stimuli and kinase regulators of the Hippo pathway remain largely unknown. To identify novel regulars of the Hippo pathway, in this study we created the first ultra‐bright NanoLuc biosensor (BS) to monitor the activity of large tumor suppressor (LATS) kinase 1, a central player of the Hippo pathway. We show that this NanoLuc BS achieves significantly advanced sensitivity and stability both in vitro using purified proteins and in vivo in living cells and mice. Using this BS, we perform the first kinome‐wide screen and identify many kinases regulating LATS and its effectors yes‐associated protein (YAP) and transcriptional co‐activator with PDZ‐ binding motif (TAZ). We also show for the first time that activation of receptor tyrosine kinase anaplastic lymphoma kinase (ALK) by its extracellular ligand family with sequence similarity (FAM)150 activates Hippo effector YAP/TAZ by increasing their nuclear translocation. Significantly, we show that constitutively active ALK induces tumorigenic phenotypes, such as increased cancer cell proliferation/colony formation via YAP/TAZ and elevated immune evasion via YAP/TAZ‐programmed death‐ligand 1 in breast and lung cancer cells. In summary, we have developed a new LATS BS for cancer biology and therapeutics research and uncovered a novel ALK‐LATS‐YAP/TAZ signaling axis that may play important roles in cancer and possibly other biologic processes.—Nouri, K., Azad, T., Lightbody, E., Khanal, P., Nicol, C. J., Yang, X. A kinome‐wide screen using a NanoLuc LATS luminescent biosensor identifies ALK as a novel regulator of the Hippo pathway in tumorigenesis and immune evasion. FASEB J. 33, 12487–12499 (2019). http://www.fasebj.org

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“…However, because treatment with EGFR inhibitors can lead to the development of mutations conferring resistance to such treatments (e.g., T790M), these drugs have limited therapeutic e cacy in lung cancer [4,5]. Anaplastic lymphoma kinase [6,7], ROS proto-oncogene1 [8,9], neurotrophic receptor tyrosine kinases [10][11][12] and the B-Raf proto-oncogene [13,14] have also emerged as possible therapeutic targets for lung cancer, but drugs based on these targets are less common, and further study of their side effects is still required. Hence, the development of targeted drugs…”

Section: Introductionmentioning

confidence: 99%

Expression of HYOU1 via reciprocal crosstalk between NSCLC cells and HUVECs control cancer progression and chemoresistance in multicellular tumor spheroids

Lee

Song

Choi

et al. 2020

Preprint

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Background Among all cancer types, lung cancer ranks highest worldwide in terms of both incidence and mortality. The crosstalk between lung cancer cells and their tumor microenvironment (TME) has begun to emerge as the “Achilles heel” of the disease and thus constitutes an attractive target for anticancer therapy. We previously revealed that crosstalk between lung cancer cells and endothelial cells (ECs) induces chemoresistance in multicellular tumor spheroids (MCTSs). Methods In this study, we idientified that factors secreted in response to crosstalk between ECs and lung cancer cells play pivotal roles in the development of chemoresistance in lung cancer spheroids. Results We determined that the expression of hypoxia up-regulated protein 1 (HYOU1) in lung cancer spheroids was increased by factors secreted in response to crosstalk between ECs and lung cancer cells. Direct interaction between lung cancer cells and ECs also caused an elevation in the expression of HYOU1 in MCTSs. Inhibition of HYOU1 expression not only suppressed stemness and malignancy, but also facilitated apoptosis and chemosensitivity in lung cancer MCTSs. Inhibition of HYOU1 expression also significantly increased the expression of interferon signaling components in lung cancer cells. Moreover, the activation of the PI3K/AKT/mTOR pathway was involved in the HYOU1-induced aggression of lung cancer cells. Conclusion Taken together, our results identify HYOU1, which is induced in response to crosstalk between ECs and lung cancer cells within the TME, as a potential therapeutic target for combating the aggressive behavior of cancer cells.

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Role and targeting of anaplastic lymphoma kinase in cancer

Cited by 75 publications

References 73 publications

An Anaplastic Lymphoma Kinase Pathway Signature is associated with Cell De-differentiation, Neoadjuvant Response and Recurrence Risk in Breast Cancer

An Anaplastic Lymphoma Kinase Pathway Signature is associated with Cell De-differentiation, Neoadjuvant Response and Recurrence Risk in Breast Cancer

A kinome‐wide screen using a NanoLuc LATS luminescent biosensor identifies ALK as a novel regulator of the Hippo pathway in tumorigenesis and immune evasion

Expression of HYOU1 via reciprocal crosstalk between NSCLC cells and HUVECs control cancer progression and chemoresistance in multicellular tumor spheroids

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