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16 pages, 6214 KiB

Open AccessArticle

The Differential Impact of SRC Expression on the Prognosis of Patients with Head and Neck Squamous Cell Carcinoma

by Francisco Hermida-Prado, Rocío Granda-Díaz, Nagore del-Río-Ibisate, M. Ángeles Villaronga, Eva Allonca, Irati Garmendia, Luis M. Montuenga, René Rodríguez, Aitana Vallina, César Alvarez-Marcos, Juan P. Rodrigo and Juana M. García-Pedrero

Cancers 2019, 11(11), 1644; https://doi.org/10.3390/cancers11111644 - 25 Oct 2019

Cited by 9 | Viewed by 2788

Abstract

Aberrant SRC expression and activation is frequently detected in multiple cancers, and hence, targeting SRC has emerged as a promising therapeutic strategy. Different SRC inhibitors have demonstrated potent anti-tumor activity in preclinical models, although they largely lack clinical efficacy as monotherapy in late-stage [...] Read more.

Aberrant SRC expression and activation is frequently detected in multiple cancers, and hence, targeting SRC has emerged as a promising therapeutic strategy. Different SRC inhibitors have demonstrated potent anti-tumor activity in preclinical models, although they largely lack clinical efficacy as monotherapy in late-stage solid tumors, including head and neck squamous cell carcinomas (HNSCC). Adequate selection and stratification of patients who may respond to and benefit from anti-SRC therapies is therefore needed to guide clinical trials and treatment efficacy. This study investigates the prognostic significance of active SRC expression in a homogeneous cohort of 122 human papillomavirus (HPV)-negative, surgically treated HNSCC patients. Immunohistochemical evaluation of the active form of SRC by means of anti-SRC Clone 28 monoclonal antibody was specifically performed and subsequently correlated with clinical data. The expression of p-SRC (Tyr419), total SRC, and downstream SRC effectors was also analyzed. Our results uncovered striking differences in the prognostic relevance of SRC expression in HNSCC patients depending on the tumor site. Active SRC expression was found to significantly associate with advanced disease stages, presence of lymph node metastasis, and tumor recurrences in patients with laryngeal tumors, but not in the pharyngeal subgroup. Multivariate Cox analysis further revealed active SRC expression as an independent predictor of cancer-specific mortality in patients with laryngeal carcinomas. Concordantly, expression of p-SRC (Tyr419) and the SRC substrates focal adhesion kinase (FAK) and the Arf GTPase-activating protein ASAP1 also showed specific associations with poor prognosis in the larynx. These findings could have important implications in ongoing Src family kinase (SFK)-based clinical trials, as these new criteria could help to improve patient selection and develop biomarker-stratified trials. Full article

(This article belongs to the Special Issue The Role of Src Kinase Family in Cancer)

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Review

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36 pages, 12186 KiB

Open AccessFeature PaperReview

Three-Dimensional Interactions Analysis of the Anticancer Target c-Src Kinase with Its Inhibitors

by Vibhu Jha, Marco Macchia, Tiziano Tuccinardi and Giulio Poli

Cancers 2020, 12(8), 2327; https://doi.org/10.3390/cancers12082327 - 18 Aug 2020

Cited by 10 | Viewed by 3947

Abstract

Src family kinases (SFKs) constitute the biggest family of non-receptor tyrosine kinases considered as therapeutic targets for cancer therapy. An aberrant expression and/or activation of the proto-oncogene c-Src kinase, which is the oldest and most studied member of the family, has long been [...] Read more.

Src family kinases (SFKs) constitute the biggest family of non-receptor tyrosine kinases considered as therapeutic targets for cancer therapy. An aberrant expression and/or activation of the proto-oncogene c-Src kinase, which is the oldest and most studied member of the family, has long been demonstrated to play a major role in the development, growth, progression and metastasis of numerous human cancers, including colon, breast, gastric, pancreatic, lung and brain carcinomas. For these reasons, the pharmacological inhibition of c-Src activity represents an effective anticancer strategy and a few compounds targeting c-Src, together with other kinases, have been approved as drugs for cancer therapy, while others are currently undergoing preclinical studies. Nevertheless, the development of potent and selective inhibitors of c-Src aimed at properly exploiting this biological target for the treatment of cancer still represents a growing field of study. In this review, the co-crystal structures of c-Src kinase in complex with inhibitors discovered in the past two decades have been described, highlighting the key ligand–protein interactions necessary to obtain high potency and the features to be exploited for addressing selectivity and drug resistance issues, thus providing useful information for the design of new and potent c-Src kinase inhibitors. Full article

(This article belongs to the Special Issue The Role of Src Kinase Family in Cancer)

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20 pages, 2508 KiB

Open AccessReview

Src Family Tyrosine Kinases in Intestinal Homeostasis, Regeneration and Tumorigenesis

by Audrey Sirvent, Rudy Mevizou, Dana Naim, Marie Lafitte and Serge Roche

Cancers 2020, 12(8), 2014; https://doi.org/10.3390/cancers12082014 - 23 Jul 2020

Cited by 15 | Viewed by 3349

Abstract

Src, originally identified as an oncogene, is a membrane-anchored tyrosine kinase and the Src family kinase (SFK) prototype. SFKs regulate the signalling induced by a wide range of cell surface receptors leading to epithelial cell growth and adhesion. In the intestine, the SFK [...] Read more.

Src, originally identified as an oncogene, is a membrane-anchored tyrosine kinase and the Src family kinase (SFK) prototype. SFKs regulate the signalling induced by a wide range of cell surface receptors leading to epithelial cell growth and adhesion. In the intestine, the SFK members Src, Fyn and Yes regulate epithelial cell proliferation and migration during tissue regeneration and transformation, thus implicating conserved and specific functions. In patients with colon cancer, SFK activity is a marker of poor clinical prognosis and a potent driver of metastasis formation. These tumorigenic activities are linked to SFK capacity to promote the dissemination and tumour-initiating capacities of epithelial tumour cells. However, it is unclear how SFKs promote colon tumour formation and metastatic progression because SFK-encoding genes are unfrequently mutated in human cancer. Here, we review recent findings on SFK signalling during intestinal homeostasis, regeneration and tumorigenesis. We also describe the key nongenetic mechanisms underlying SFK tumour activities in colorectal cancer, and discuss how these mechanisms could be exploited in therapeutic strategies to target SFK signalling in metastatic colon cancer. Full article

(This article belongs to the Special Issue The Role of Src Kinase Family in Cancer)

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18 pages, 1106 KiB

Open AccessReview

SRC-Family Kinases in Acute Myeloid Leukaemia and Mastocytosis

by Edwige Voisset, Fabienne Brenet, Sophie Lopez and Paulo de Sepulveda

Cancers 2020, 12(7), 1996; https://doi.org/10.3390/cancers12071996 - 21 Jul 2020

Cited by 9 | Viewed by 3230

Abstract

Protein tyrosine kinases have been recognized as important actors of cell transformation and cancer progression, since their discovery as products of viral oncogenes. SRC-family kinases (SFKs) play crucial roles in normal hematopoiesis. Not surprisingly, they are hyperactivated and are essential for membrane receptor [...] Read more.

Protein tyrosine kinases have been recognized as important actors of cell transformation and cancer progression, since their discovery as products of viral oncogenes. SRC-family kinases (SFKs) play crucial roles in normal hematopoiesis. Not surprisingly, they are hyperactivated and are essential for membrane receptor downstream signaling in hematological malignancies such as acute myeloid leukemia (AML) and mastocytosis. The precise roles of SFKs are difficult to delineate due to the number of substrates, the functional redundancy among members, and the use of tools that are not selective. Yet, a large num ber of studies have accumulated evidence to support that SFKs are rational therapeutic targets in AML and mastocytosis. These two pathologies are regulated by two related receptor tyrosine kinases, which are well known in the field of hematology: FLT3 and KIT. FLT3 is one of the most frequently mutated genes in AML, while KIT oncogenic mutations occur in 80–90% of mastocytosis. Studies on oncogenic FLT3 and KIT signaling have shed light on specific roles for members of the SFK family. This review highlights the central roles of SFKs in AML and mastocytosis, and their interconnection with FLT3 and KIT oncoproteins. Full article

(This article belongs to the Special Issue The Role of Src Kinase Family in Cancer)

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21 pages, 1135 KiB

Open AccessReview

Targeting SRC Family Kinases in Mesothelioma: Time to Upgrade

by Paola Indovina, Iris Maria Forte, Francesca Pentimalli and Antonio Giordano

Cancers 2020, 12(7), 1866; https://doi.org/10.3390/cancers12071866 - 11 Jul 2020

Cited by 6 | Viewed by 3184

Abstract

Malignant mesothelioma (MM) is a deadly tumor mainly caused by exposure to asbestos. Unfortunately, no current treatment is able to change significantly the natural history of the disease, which has a poor prognosis in the majority of patients. The non-receptor tyrosine kinase SRC [...] Read more.

Malignant mesothelioma (MM) is a deadly tumor mainly caused by exposure to asbestos. Unfortunately, no current treatment is able to change significantly the natural history of the disease, which has a poor prognosis in the majority of patients. The non-receptor tyrosine kinase SRC and other SRC family kinase (SFK) members are frequently hyperactivated in many cancer types, including MM. Several works have indeed suggested that SFKs underlie MM cell proliferation, survival, motility, and invasion, overall affecting multiple oncogenic pathways. Consistently, SFK inhibitors effectively counteracted MM cancerous features at the preclinical level. Dasatinib, a multi-kinase inhibitor targeting SFKs, was also assessed in clinical trials either as second-line treatment for patients with unresectable MM or, more recently, as a neoadjuvant agent in patients with resectable MM. Here, we provide an overview of the molecular mechanisms implicating SFKs in MM progression and discuss possible strategies for a more successful clinical application of SFK inhibitors. Our aim is to stimulate discussion and further consideration of these agents in better designed preclinical and clinical studies to make the most of another class of powerful antitumoral drugs, which too often are lost in translation when applied to MM. Full article

(This article belongs to the Special Issue The Role of Src Kinase Family in Cancer)

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21 pages, 1214 KiB

Open AccessReview

SRC Kinase in Glioblastoma: News from an Old Acquaintance

by Claudia Cirotti, Claudia Contadini and Daniela Barilà

Cancers 2020, 12(6), 1558; https://doi.org/10.3390/cancers12061558 - 12 Jun 2020

Cited by 34 | Viewed by 3486

Abstract

Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) [...] Read more.

Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness. Full article

(This article belongs to the Special Issue The Role of Src Kinase Family in Cancer)

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16 pages, 897 KiB

Open AccessReview

c-Src and EGFR Inhibition in Molecular Cancer Therapy: What Else Can We Improve?

by Stefania Belli, Daniela Esposito, Alberto Servetto, Ada Pesapane, Luigi Formisano and Roberto Bianco

Cancers 2020, 12(6), 1489; https://doi.org/10.3390/cancers12061489 - 07 Jun 2020

Cited by 38 | Viewed by 5536

Abstract

The proto-oncogene c-Src is a non-receptor tyrosine kinase playing a key role in many cellular pathways, including cell survival, migration and proliferation. c-Src de-regulation has been observed in several cancer types, making it an appealing target for drug discovery efforts. Recent evidence emphasizes [...] Read more.

The proto-oncogene c-Src is a non-receptor tyrosine kinase playing a key role in many cellular pathways, including cell survival, migration and proliferation. c-Src de-regulation has been observed in several cancer types, making it an appealing target for drug discovery efforts. Recent evidence emphasizes its crucial role not only in promoting oncogenic traits, but also in the acquisition and maintenance of cancer resistance to various chemotherapeutic or molecular target drugs. c-Src modulates epidermal growth factor receptor (EGFR) activation and amplifies its downstream oncogenic signals. In this review, we report several studies supporting c-Src kinase role in the intricate mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs). We further highlighted pre- and clinical progresses of combined treatment strategies made in recent years. Several pre-clinical data have encouraged the use of c-Src inhibitors in combination with EGFR inhibitors. However, clinical trials provided controversial outcomes in some cancer types. Despite c-Src inhibitors showed good tolerability in cancer patients, no incontrovertible and consistent clinical responses were recorded, supporting the idea that a better selection of patients is needed to improve clinical outcome. Currently, the identification of biological markers predictive of therapy response and the accurate molecular screening of cancer patients aimed to gain most clinical benefits become decisive and mandatory. Full article

(This article belongs to the Special Issue The Role of Src Kinase Family in Cancer)

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28 pages, 391 KiB

Open AccessFeature PaperReview

Src Family Kinases as Therapeutic Targets in Advanced Solid Tumors: What We Have Learned So Far

by Stefano Martellucci, Letizia Clementi, Samantha Sabetta, Vincenzo Mattei, Lorenzo Botta and Adriano Angelucci

Cancers 2020, 12(6), 1448; https://doi.org/10.3390/cancers12061448 - 02 Jun 2020

Cited by 76 | Viewed by 5347

Abstract

Src is the prototypal member of Src Family tyrosine Kinases (SFKs), a large non-receptor kinase class that controls multiple signaling pathways in animal cells. SFKs activation is necessary for the mitogenic signal from many growth factors, but also for the acquisition of migratory [...] Read more.

Src is the prototypal member of Src Family tyrosine Kinases (SFKs), a large non-receptor kinase class that controls multiple signaling pathways in animal cells. SFKs activation is necessary for the mitogenic signal from many growth factors, but also for the acquisition of migratory and invasive phenotype. Indeed, oncogenic activation of SFKs has been demonstrated to play an important role in solid cancers; promoting tumor growth and formation of distant metastases. Several drugs targeting SFKs have been developed and tested in preclinical models and many of them have successfully reached clinical use in hematologic cancers. Although in solid tumors SFKs inhibitors have consistently confirmed their ability in blocking cancer cell progression in several experimental models; their utilization in clinical trials has unveiled unexpected complications against an effective utilization in patients. In this review, we summarize basic molecular mechanisms involving SFKs in cancer spreading and metastasization; and discuss preclinical and clinical data highlighting the main challenges for their future application as therapeutic targets in solid cancer progression Full article

(This article belongs to the Special Issue The Role of Src Kinase Family in Cancer)

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24 pages, 1784 KiB

Open AccessReview

The Crosstalk between Src and Hippo/YAP Signaling Pathways in Non-Small Cell Lung Cancer (NSCLC)

by Ping-Chih Hsu, Cheng-Ta Yang, David M. Jablons and Liang You

Cancers 2020, 12(6), 1361; https://doi.org/10.3390/cancers12061361 - 26 May 2020

Cited by 37 | Viewed by 9770

Abstract

The advancement of new therapies, including targeted therapies and immunotherapies, has improved the survival of non-small-cell lung cancer (NSCLC) patients in the last decade. Some NSCLC patients still do not benefit from therapies or encounter progressive disease during the course of treatment because [...] Read more.

The advancement of new therapies, including targeted therapies and immunotherapies, has improved the survival of non-small-cell lung cancer (NSCLC) patients in the last decade. Some NSCLC patients still do not benefit from therapies or encounter progressive disease during the course of treatment because they have intrinsic resistance, acquired resistance, or lack a targetable driver mutation. More investigations on the molecular biology of NSCLC are needed to find useful biomarkers for current therapies and to develop novel therapeutic strategies. Src is a non-receptor tyrosine kinase protein that interacts with cell surface growth factor receptors and the intracellular signaling pathway to maintain cell survival tumorigenesis in NSCLC. The Yes-associated protein (YAP) is one of the main effectors of the Hippo pathway and has been identified as a promoter of drug resistance, cancer progression, and metastasis in NSCLC. Here, we review studies that have investigated the activation of YAP as mediated by Src kinases and demonstrate that Src regulates YAP through three main mechanisms: (1) direct phosphorylation; (2) the activation of pathways repressing Hippo kinases; and (3) Hippo-independent mechanisms. Further work should focus on the efficacy of Src inhibitors in inhibiting YAP activity in NSCLC. In addition, future efforts toward developing potentially reasonable combinations of therapy targeting the Src–YAP axis using other therapies, including targeted therapies and/or immunotherapies, are warranted. Full article

(This article belongs to the Special Issue The Role of Src Kinase Family in Cancer)

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26 pages, 1210 KiB

Open AccessReview

Regulation of Src Family Kinases during Colorectal Cancer Development and Its Clinical Implications

by Wook Jin

Cancers 2020, 12(5), 1339; https://doi.org/10.3390/cancers12051339 - 23 May 2020

Cited by 50 | Viewed by 8360

Abstract

Src family kinases (SFKs) are non-receptor kinases that play a critical role in the pathogenesis of colorectal cancer (CRC). The expression and activity of SFKs are upregulated in patients with CRC. Activation of SFKs promotes CRC cell proliferation, metastases to other organs and [...] Read more.

Src family kinases (SFKs) are non-receptor kinases that play a critical role in the pathogenesis of colorectal cancer (CRC). The expression and activity of SFKs are upregulated in patients with CRC. Activation of SFKs promotes CRC cell proliferation, metastases to other organs and chemoresistance, as well as the formation of cancer stem cells (CSCs). The enhanced expression level of Src is associated with decreased survival in patients with CRC. Src-mediated regulation of CRC progression involves various membrane receptors, modulators, and suppressors, which regulate Src activation and its downstream targets through various mechanisms. This review provides an overview of the current understanding of the correlations between Src and CRC progression, with a special focus on cancer cell proliferation, invasion, metastasis and chemoresistance, and formation of CSCs. Additionally, this review discusses preclinical and clinical strategies to improve the therapeutic efficacy of drugs targeting Src for treating patients with CRC. Full article

(This article belongs to the Special Issue The Role of Src Kinase Family in Cancer)

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