YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib

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Abstract

Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer.Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC.Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples.Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer.Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy.

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Most cited references 30

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Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays.

Louis Lombardo, Francis Y Lee, Ping Chen … (2004)

A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.

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Src kinases as therapeutic targets for cancer.

Lori C Kim, Lanxi Song, Eric B. Haura (2009)

Src family kinases (SFKs) have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development. SFKs comprise nine family members that share similar structure and function. Overexpression or high activation of SFKs occurs frequently in tumor tissues and they are central mediators in multiple signaling pathways that are important in oncogenesis. SFKs can interact with tyrosine kinase receptors, such as EGFR and the VEGF receptor. SFKs can affect cell proliferation via the Ras/ERK/MAPK pathway and can regulate gene expression via transcription factors such as STAT molecules. SFKs can also affect cell adhesion and migration via interaction with integrins, actins, GTPase-activating proteins, scaffold proteins, such as p130(CAS) and paxillin, and kinases such as focal adhesion kinases. Furthermore, SFKs can regulate angiogenesis via gene expression of angiogenic growth factors, such as fibroblast growth factor, VEGF, and interleukin 8. On the basis of these important findings, small-molecule SFK inhibitors have been developed and are undergoing early phase clinical testing. In preclinical studies these agents can suppress tumor growth and metastases. The agents seem to be safe in humans and could add to the therapeutic arsenal against subsets of cancers.

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Refining the treatment of NSCLC according to histological and molecular subtypes.

Anish Thomas, Stephen V. Liu, Deepa Subramaniam … (2015)

In the past decade, the characterization of non-small-cell lung cancer (NSCLC) into subtypes based on genotype and histology has resulted in dramatic improvements in disease outcome in select patient subgroups. In particular, molecularly targeted agents that inhibit EGFR or ALK are approved for the treatment of NSCLC harbouring genetic alterations in the genes encoding these proteins. Although acquired resistance usually limits the duration of response to these therapies, a number of new agents have proven effective at tackling specific resistance mechanisms to first-generation inhibitors. Large initiatives are starting to address the role of biomarker-driven targeted therapy in squamous lung cancers, and in the adjuvant setting. Immunotherapy undeniably holds great promise and our understanding of subsets of NSCLC based on patterns of immune response is continuing to evolve. In addition, efforts are underway to identify rare genomic subsets through genomic screening, functional studies, and molecular characterization of exceptional responders. This Review provides an overview of the key developments in the treatment of NSCLC, and discusses potential strategies to further optimize therapy by targeting disease subtypes.

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Author and article information

Journal

Title: American Journal of Respiratory and Critical Care Medicine

Abbreviated Title: Am J Respir Crit Care Med

Publisher: American Thoracic Society

ISSN (Print): 1073-449X

ISSN (Electronic): 1535-4970

Publication date Created: October 01 2019

Publication date (Print): October 01 2019

Volume: 200

Issue: 7

Pages: 888-899

Affiliations

[1 ]Program in Solid Tumors, Center for Applied Medical Research, Pamplona, Spain

[2 ]Department of Pathology, Anatomy, and Physiology, School of Medicine and

[3 ]Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain

[4 ]Navarra Health Research Institute, Pamplona, Spain

[5 ]Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain

[6 ]Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain

[7 ]Lung Cancer Clinical Research Unit and Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

[8 ]Department of Translational Molecular Pathology and

[9 ]Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas

[10 ]Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas, University of Salamanca, Salamanca, Spain

[11 ]Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain

[12 ]Medical School, Universidad Complutense, Madrid, Spain

[13 ]Medical Oncology Department, Clínica Universidad de Navarra, Pamplona, Spain

[14 ]Oncology Department, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Barcelona, Spain; and

[15 ]Cancer Epigenetics and Biology Program, Genes and Cancer Group, Bellvitge Biomedical Research Institute, Hospitalet de Llobregat, Barcelona, Spain

Article

DOI: 10.1164/rccm.201807-1292OC

PubMed ID: 31166114

SO-VID: 5f40feb1-ca72-4f65-a077-a6d2d10a2c4c

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YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib

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Most cited references 30

Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays.

Src kinases as therapeutic targets for cancer.

Refining the treatment of NSCLC according to histological and molecular subtypes.

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