Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells

Poh, Ashleigh R.; O’Donoghue, Robert J.J.; Ernst, Matthias

doi:10.18632/oncotarget.4199

Cited by 108 publications

(99 citation statements)

References 189 publications

(166 reference statements)

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“…HCK, a Src family tyrosine kinase and a direct target of ibrutinib, could enhance tumor‐associated macrophage migration and matrix remodeling to promote invasive capacity of tumor cells in a MMP‐dispensable manner . Although there is no related studies regarding the biological functions of HCK in HCC, it has been reported that HCK activation played important roles in podosome formation which contributed to cancer cell dissociation from the primary tumor and seeding into distal organs . The mutation of p.V174M in HCK takes place in the SH2 domain, which conformation is crucial for the HCK protein activation; therefore, this mutation may lead to abnormal activation of HCK, which could promote tumor cell invasion.…”

Section: Resultsmentioning

confidence: 99%

Circulating tumor DNA profiling reveals clonal evolution and real‐time disease progression in advanced hepatocellular carcinoma

Cai

Chen

Zeng

et al. 2017

Intl Journal of Cancer

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Circulating tumor DNA (ctDNA) provides a potential non-invasive biomarker for cancer diagnosis and prognosis, but whether it could reflect tumor heterogeneity and monitor therapeutic responses in hepatocellular carcinoma (HCC) is unclear. Focusing on 574 cancer genes known to harbor actionable mutations, we identified the mutation repertoire of HCC tissues, and monitored the corresponding ctDNA features in blood samples to evaluate its clinical significance. Analysis of 3 HCC patients' mutation profiles revealed that ctDNA could overcome tumor heterogeneity and provide information of tumor burden and prognosis. Further analysis was conducted on the 4th HCC case with multiple lesion samples and sequential plasma samples. We identified 160 subclonal SNVs in tumor tissues as well as matched peritumor tissues with PBMC as control. 96.9% of this patient's tissue mutations could be also detected in plasma samples. These subclonal SNVs were grouped into 9 clusters according to their trends of cellular prevalence shift in tumor tissues. Two clusters constituted of tumor stem somatic mutations showed circulating levels relating with cancer progression. Analysis of tumor somatic mutations revealed that circulating level of such tumor stem somatic mutations could reflect tumor burden and even predict prognosis earlier than traditional strategies. Furthermore, HCK (p.V174M), identified as a recurrent/metastatic related mutation site, could promote migration and invasion of HCC cells. Taken together, study of mutation profiles in biopsy and plasma samples in HCC patients showed that ctDNA could overcome tumor heterogeneity and real-time track the therapeutic responses in the longitudinal monitoring.Hepatocellular carcinoma (HCC), one of the extraordinarily heterogeneous malignancy diseases, ranks the third leading cause of cancer-related death in China. 1 Unlike most other solid tumors, majority of HCC cases were developed with a history of cirrhosis due to chronic HBV or HCV infections. 2,3 Surgical resection was demonstrated to be the first choice for HCC treatment according to the clinical experiences of the past 50 years. 4 However, the prognosis of HCC remains poor owing to high recurrent/metastatic rate after curative resection, since some of these patients could develop multiple tumor lesions, portal vein tumor thrombus (PVTT), lymph node metastases or other distant metastases. 5,6 The majority

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Section: Resultsmentioning

confidence: 99%

Circulating tumor DNA profiling reveals clonal evolution and real‐time disease progression in advanced hepatocellular carcinoma

Cai

Chen

Zeng

et al. 2017

Intl Journal of Cancer

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“…By contrast, excessive activation of endogenous SFK results in a lethal autoimmune response in Lyn CA mice (Hibbs et al, 1995) and inflammatory lung disease in Hck CA mice (Ernst et al, 2002). The latter phenotype can be rationalized by the presence of Wasp, Cbl, paxilin, and other Hck substrates in adhesion and migration complexes (Poh et al, 2015), and the capacity of Hck to mediate β1/2 integrin-dependent outside-in signaling and to facilitate the formation of podosomes (Kovács et al, 2014). However, we note that despite the more aggressive growth of tumors in Hck CA , the extent of TAMs remained comparable.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression

Poh¹,

Love²,

Masson³

et al. 2017

Cancer Cell

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SUMMARY Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling. Accordingly, pharmacological inhibition or genetic reduction of Hck activity suppresses alternative activation of tumor-associated macrophages and the growth of colon cancer xenografts. Thus, Hck may serve as a promising therapeutic target for solid malignancies.

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“…Several scaffolds for targeted HCK inhibition are in development based on prior work implicating HCK in the pathogenesis of several solid and hematologic malignancies, as well as productive HIV infection. 41,42 In addition to inhibiting other SRC family members, dasatinib also shows potent inhibition of HCK and may be active in diseases dependent on mutated MYD88. 43 In conclusion, our findings suggest that HCK is a downstream target of mutated MYD88, is activated by IL-6, and triggers pro-survival signaling including PI3K/AKT, MAPK/ERK, and BTK in MYD88-mutated cells.…”

Section: Cc-292mentioning

confidence: 99%

HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib

Yang

Buhrlage

et al. 2016

Blood

115

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Key Points• HCK transcription and activation is triggered by mutated MYD88, and is an important determinant of pro-survival signaling.• HCK is also a target of ibrutinib, and inhibition of its kinase activity triggers apoptosis in mutated MYD88 cells.Activating mutations in MYD88 are present in ∼95% of patients with Waldenström macroglobulinemia (WM), as well as other B-cell malignancies including activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL). In WM, mutated MYD88 triggers activation of Bruton tyrosine kinase (BTK). Ibrutinib, a pleiotropic kinase inhibitor that targets BTK, is highly active in patients with mutated MYD88. We observed that mutated MYD88 WM and ABC DLBCL cell lines, as well as primary WM cells show enhanced hematopoietic cell kinase (HCK) transcription and activation, and that HCK is activated by interleukin 6 (IL-6). Over-expression of mutated MYD88 triggers HCK and IL-6 transcription, whereas knockdown of HCK reduced survival and attenuated BTK, phosphoinositide 3-kinase/ AKT, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in mutated MYD88 WM and/or ABC DLBCL cells. Ibrutinib and the more potent HCK inhibitor A419259, blocked HCK activation and induced apoptosis in mutated MYD88 WM and ABC DLBCL cells. Docking and pull-down studies confirmed that HCK was a target of ibrutinib. Ibrutinib and A419259 also blocked adenosine triphosphate binding to HCK, whereas transduction of mutated MYD88 expressing WM cells with a mutated HCK gatekeeper greatly increased the half maximal effective concentration for ibrutinib and A419259. The findings support that HCK expression and activation is triggered by mutated MYD88, supports the growth and survival of mutated MYD88 WM and ABC DLBCL cells, and is a direct target of ibrutinib. HCK represents a novel target for therapeutic development in MYD88-mutated WM and ABC DLBCL, and possibly other diseases driven by mutated MYD88. (Blood. 2016;127(25):3237-3252)

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Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells

Cited by 108 publications

References 189 publications

Circulating tumor DNA profiling reveals clonal evolution and real‐time disease progression in advanced hepatocellular carcinoma

Circulating tumor DNA profiling reveals clonal evolution and real‐time disease progression in advanced hepatocellular carcinoma

Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression

HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib

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