Crk and CrkL as Therapeutic Targets for Cancer Treatment

Park, Tae‐Ju

doi:10.3390/cells10040739

Cited by 29 publications

(26 citation statements)

References 120 publications

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“…In addition, ACPSVs may also play a role in the metastatic process, due to their ability to potentially disrupt normal tissue structure by stimulating proliferation in normal tissue cells, causing them to dissolve their cellular junctions during the proliferation process, ultimately allowing tumor cells to invade normal tissue. In line with our data that ACPSVs are prevalent in solid tumors and consistent with the notion that ACPSVs may play pivotal roles in tumor biogenesis and metastasis, Crk and JNK have been reported to be overexpressed in tumors, and is associated with tumorigenesis, tumor progression, and poor prognosis with reduced survival rates in many cancers, including oral squamous cell carcinoma 24 – 29 . Further supporting this hypothesis, mice lacking JNK1 displayed decreased tumor cell proliferation in a mouse model of liver carcinogenesis 30 , and JNK inhibition was found to result in reduction in cell proliferation and capillary tube formation in oral cancer 31 .…”

Section: Discussionsupporting

confidence: 92%

Presence of CrkI-containing microvesicles in squamous cell carcinomas could have ramifications on tumor biology and cancer therapeutics

Mohamed

Al‐Khudari

Cassini‐Vieira

et al. 2022

Sci Rep

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Recently, we described a phenomenon whereby apoptotic cells generate and release CrkI-containing microvesicles, which stimulate proliferation in surrounding cells upon contact to compensate for their own demise. We termed these microvesicles “ACPSVs” for Apoptotic Compensatory Proliferation Signaling microvesicles. As immune cells and a majority of current cancer therapeutics destroy tumor cells primarily by apoptosis, we conducted a small pilot study to assess the possibility that ACPSVs may also be generated in squamous cell carcinomas. We first evaluated a primary and a metastatic squamous cell carcinoma cancer cell lines for their ability to produce ACPSVs under normal and apoptotic conditions. We next conducted a pilot study to assess the occurrence of ACPSVs in solid tumors extracted from 20 cancer patients with squamous cell carcinomas. Both cancer cell lines produced copious amounts of ACPSVs under apoptotic conditions. Interestingly, the metastatic squamous cell carcinoma cancer cell line also produced high levels of ACPSVs under healthy condition, suggesting that the ability to generate ACPSVs may be hijacked by these cells. Importantly, ACPSVs were also abundant in the solid tumors of all squamous cell carcinoma cancer patients. Detection of ACPSVs in cancer has potentially important ramifications in tumor biology and cancer therapeutics which warrants further investigation.

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Section: Discussionsupporting

confidence: 92%

Presence of CrkI-containing microvesicles in squamous cell carcinomas could have ramifications on tumor biology and cancer therapeutics

Mohamed

Al‐Khudari

Cassini‐Vieira

et al. 2022

Sci Rep

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“…CRKL is an adaptor protein with an array of reported functions involving human development, immune cell migration, and signal transduction pathways. 50 Overexpression of CRKL has been reported in various cancers and is associated with a poor prognosis. 51 52 In laryngeal squamous cell carcinoma, CRKL amplification is associated with increased nuclear expression of CRKL, a requirement for tumor cell viability.…”

Section: Discussionmentioning

confidence: 99%

Clinical, genomic, and transcriptomic correlates of response to immune checkpoint blockade-based therapy in a cohort of patients with angiosarcoma treated at a single center

Rosenbaum

Antonescu

Smith

et al. 2022

J Immunother Cancer

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BackgroundAngiosarcoma is a histologically and molecularly heterogeneous vascular neoplasm with aggressive clinical behavior. Emerging data suggests that immune checkpoint blockade (ICB) is efficacious against some angiosarcomas, particularly cutaneous angiosarcoma of the head and neck (CHN).MethodsPatients with histologically confirmed angiosarcoma treated with ICB-based therapy at a comprehensive cancer center were retrospectively identified. Clinical characteristics and the results of targeted exome sequencing, transcriptome sequencing, and immunohistochemistry analyses were examined for correlation with clinical benefit. Durable clinical benefit was defined as a progression-free survival (PFS) of ≥16 weeks.ResultsFor the 35 patients included in the analyses, median PFS and median overall survival (OS) from the time of first ICB-based treatment were 11.9 (95% CI 7.4 to 31.9) and 42.5 (95% CI 19.6 to 114.2) weeks, respectively. Thirteen patients (37%) had PFS ≥16 weeks. Clinical factors associated with longer PFS and longer OS in multivariate analyses were ICB plus other therapy regimens, CHN disease, and white race. Three of 10 patients with CHN angiosarcoma evaluable for tumor mutational burden (TMB) had a TMB ≥10. Five of six patients with CHN angiosarcoma evaluable for mutational signature analysis had a dominant mutational signature associated with ultraviolet (UV) light. No individual gene or genomic pathway was significantly associated with PFS or OS; neither were TMB or UV signature status. Analyses of whole transcriptomes from nine patient tumor samples found upregulation of angiogenesis, inflammatory response, and KRAS signaling pathways, among others, in patients with PFS ≥16 weeks, as well as higher levels of cytotoxic T cells, dendritic cells, and natural killer cells. Patients with PFS <16 weeks had higher numbers of cancer-associated fibroblasts. Immunohistochemistry findings for 12 patients with baseline samples available suggest that neither PD-L1 expression nor presence of tumor-infiltrating lymphocytes at baseline appears necessary for a response to ICB-based therapy.ConclusionsICB-based therapy benefits only a subset of angiosarcoma patients. Patients with CHN angiosarcoma are more likely to have PFS ≥16 weeks, a dominant UV mutational signature, and higher TMB than angiosarcomas arising from other primary sites. However, clinical benefit was seen in other angiosarcomas also and was not restricted to tumors with a high TMB, a dominant UV signature, PD-L1 expression, or presence of tumor infiltrating lymphocytes at baseline.

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“…Crkl is a ubiquitously expressed 39 kDa adapter protein, member of the protooncogene CRK family, that mediates and regulates the linking of several signaling proteins. It was originally discovered in cells from patients with chronic myelogenous leukemia, and its overexpression is correlated with the onset of a number of cancer diseases (recently reviewed in [1]). Crkl plays an essential role in regulating several physiological pathways linked to cytoskeletal changes and cell migration and possesses a prominent role in the onset of human cancers, such as, for example, chronic myelogenous leukemia [2].…”

Section: Introductionmentioning

confidence: 99%

Experimental Characterization of the Interaction between the N-Terminal SH3 Domain of Crkl and C3G

Pagano

Malagrinò

Nardella

et al. 2021

IJMS

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Crkl is a protein involved in the onset of several cancer pathologies that exerts its function only through its protein–protein interaction domains, a SH2 domain and two SH3 domains. SH3 domains are small protein interaction modules that mediate the binding and recognition of proline-rich sequences. One of the main physiological interactors of Crkl is C3G (also known as RAPGEF1), an interaction with key implications in regulating cellular growth and differentiation, cell morphogenesis and adhesion processes. Thus, understanding the interaction between Crkl and C3G is fundamental to gaining information about the molecular determinants of the several cancer pathologies in which these proteins are involved. In this paper, through a combination of fast kinetics at different experimental conditions and site-directed mutagenesis, we characterize the binding reaction between the N-SH3 domain of Crkl and a peptide mimicking a specific portion of C3G. Our results show a clear effect of pH on the stability of the complex, due to the protonation of negatively charged residues in the binding pocket of N-SH3. Our results are discussed under the light of previous work on SH3 domains.

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Crk and CrkL as Therapeutic Targets for Cancer Treatment

Cited by 29 publications

References 120 publications

Presence of CrkI-containing microvesicles in squamous cell carcinomas could have ramifications on tumor biology and cancer therapeutics

Presence of CrkI-containing microvesicles in squamous cell carcinomas could have ramifications on tumor biology and cancer therapeutics

Clinical, genomic, and transcriptomic correlates of response to immune checkpoint blockade-based therapy in a cohort of patients with angiosarcoma treated at a single center

Experimental Characterization of the Interaction between the N-Terminal SH3 Domain of Crkl and C3G

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