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Sara Mainardi, Antonio Mulero-Sánchez, Anirudh Prahallad, Giovanni Germano, Astrid Bosma, Paul Krimpenfort, Cor Lieftink, Jeffrey D Steinberg, Niels de Wit, Samuel Gonçalves-Ribeiro, Ernest Nadal, Alberto Bardelli, Alberto Villanueva, Rene Bernards
RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1-3 . Inhibition of the RAS oncoproteins has proven difficult4 , and attempts to target downstream effectors5-7 have been hampered by the activation of compensatory resistance mechanisms8 . It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10 ...
July 2018: Nature Medicine
(no author information available yet)
Targeting SHP2 suppresses ALK inhibitor resistance caused by tyrosine kinase reactivation.
May 2018: Cancer Discovery
Yu-Jing Sun, Zhong-Ling Zhuo, Hai-Peng Xian, Ke-Zhong Chen, Fan Yang, Xiao-Tao Zhao
In the clinical treatment of lung cancer, therapy failure is mainly caused by cancer metastasis and drug resistance. Here, we investigated whether the tyrosine phosphatase Shp2 is involved in the development of metastasis and drug resistance in non-small cell lung cancer (NSCLC). Shp2 was overexpressed in a subset of lung cancer tissues, and Shp2 knockdown in lung cancer cells inhibited cell proliferation and migration, downregulated c-Myc and fibronectin expression, and upregulated E-cadherin expression. In H1975 cells, which carry double mutations (L858R + T790M) in epidermal growth factor receptor (EGFR) that confers resistance toward the tyrosine kinase inhibitor gefitinib, Shp2 knockdown increased cellular sensitivity to gefitinib; conversely, in H292 cells, which express wild-type EGFR and are sensitive to gefitinib, Shp2 overexpression increased cellular resistance to gefitinib...
October 31, 2017: Oncotarget
R Srikar, Dhananjay Suresh, Ajit Zambre, Kristen Taylor, Sarah Chapman, Matthew Leevy, Anandhi Upendran, Raghuraman Kannan
A tri-block nanoparticle (TBN) comprising of an enzymatically cleavable porous gelatin nanocore encapsulated with gefitinib (tyrosine kinase inhibitor (TKI)) and surface functionalized with cetuximab-siRNA conjugate has been synthesized. Targeted delivery of siRNA to undruggable KRAS mutated non-small cell lung cancer cells would sensitize the cells to TKI drugs and offers an efficient therapy for treating cancer; however, efficient delivery of siRNA and releasing it in cytoplasm remains a major challenge. We have shown TBN can efficiently deliver siRNA to cytoplasm of KRAS mutant H23 Non-Small Cell Lung Cancer (NSCLC) cells for oncogene knockdown; subsequently, sensitizing it to TKI...
August 17, 2016: Scientific Reports
Susanne B Breitkopf, Xuemei Yang, Michael J Begley, Meghana Kulkarni, Yu-Hsin Chiu, Alexa B Turke, Jessica Lauriol, Min Yuan, Jie Qi, Jeffrey A Engelman, Pengyu Hong, Maria I Kontaridis, Lewis C Cantley, Norbert Perrimon, John M Asara
Using a series of immunoprecipitation (IP)-tandem mass spectrometry (LC-MS/MS) experiments and reciprocal BLAST, we conducted a fly-human cross-species comparison of the phosphoinositide-3-kinase (PI3K) interactome in a drosophila S2R+ cell line and several NSCLC and human multiple myeloma cell lines to identify conserved interacting proteins to PI3K, a critical signaling regulator of the AKT pathway. Using H929 human cancer cells and drosophila S2R+ cells, our data revealed an unexpected direct binding of Corkscrew, the drosophila ortholog of the non-receptor protein tyrosine phosphatase type II (SHP2) to the Pi3k21B (p60) regulatory subunit of PI3K (p50/p85 human ortholog) but no association with Pi3k92e, the human ortholog of the p110 catalytic subunit...
February 3, 2016: Scientific Reports
Xiaoye Liu, Xiaoting Yu, Jingjing Xie, Mengna Zhan, Zhuo Yu, Li Xie, Hongxiang Zeng, Feifei Zhang, Guoqiang Chen, Xianghua Yi, Junke Zheng
Immune inhibitory receptors expressed on various types of immune cells deliver inhibitory signals that maintain the homeostasis of the immune system. Recently we demonstrated that leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) and its murine homolog, paired immunoglobulin-like receptor B (PIRB), are expressed on hematopoietic stem cells and acute myeloid leukemia stem cells and function in maintenance of stemness. Herein, we determined that both LILRB2 and its soluble ligand ANGPTL2 are highly expressed in non-small cell lung cancer (NSCLC) samples, and levels are adversely related to patient prognosis...
August 28, 2015: Oncotarget
Niki Karachaliou, Rafael Rosell, Miguel Angel Molina, Santiago Viteri
Epidermal growth factor receptor (EGFR) mutations occur in 17% of non-small-cell lung cancer (NSCLC) patients with notable response to single agent therapy but with low complete remission rate and, eventually, disease progression. Priming BIM, a pro-apoptotic signaling BH3-only protein, induces sensitivity to erlotinib in EGFR-mutant cell lines. Synthetic lethal approaches and preemptive therapies based on the initial expression of BIM may significantly improve the treatment outcome. EGFR mutations result in transient pro-death imbalance of survival and apoptotic signaling in response to EGFR inhibition...
April 2014: Translational Lung Cancer Research
Jie Xu, Li-Fan Zeng, Weihua Shen, John J Turchi, Zhong-Yin Zhang
Targeted therapy with inhibitors of epidermal growth factor receptor (EGFR) has produced a noticeable benefit to non-small cell lung cancer (NSCLC) patients whose tumors carry activating mutations (e.g. L858R) in EGFR. Unfortunately, these patients develop drug resistance after treatment, due to acquired secondary gatekeeper mutations in EGFR (e.g. T790M). Given the critical role of SHP2 in growth factor receptor signaling, we sought to determine whether targeting SHP2 could have therapeutic value for EGFR inhibitor resistant NSCLC...
October 4, 2013: Biochemical and Biophysical Research Communications
Chunlan Tang, Dan Luo, Heping Yang, Qingliang Wang, Rong Zhang, Guoxiang Liu, Xiangdong Zhou
The purpose of this study was to assess the relationships between the expression of SHP2 and VEGF, VEGFR-1, VEGFR-2, MMP-2, MMP-9, TIMP-1, TIMP-2, and microvessel density (MVD), as well as the clinicopathologic parameters of these markers in non-small cell lung cancer (NSCLC). Using a tissue microarray, the expression of these 8 markers in 80 NSCLC cases was detected by immunohistochemistry. The expression of the markers was higher in cancer tissues when compared with the surrounding tissues. The MVD was lower in the CD34-positive cancer tissues than in the surrounding tissues...
October 2013: Applied Immunohistochemistry & Molecular Morphology: AIMM
C M Furcht, A R Muñoz Rojas, D Nihalani, M J Lazzara
Non-small cell lung cancer (NSCLC) cells harboring activating mutations of the epidermal growth factor receptor (EGFR) tend to display elevated activity of several survival signaling pathways. Surprisingly, these mutations also correlate with reduced phosphorylation of ERK and SHP2, a protein tyrosine phosphatase required for complete ERK activation downstream of most receptor tyrosine kinases. As ERK activity influences cellular response to EGFR inhibition, altered SHP2 function could have a role in the striking response to gefitinib witnessed with EGFR mutation...
May 2, 2013: Oncogene
Xuemei Zhan, Hongyan Dong, Chongwei Sun, Lili Liu, Dan Wang, Zhiyong Wei
BACKGROUND AND OBJECTIVE: It has been proved that protein phosphorylation and dephosphorylation were important mechanisms in lung cancer development, and tobacco smoking is an important risk factor of lung cancer. The aim of this study is to investigate the expression and clinical significance of protein tyrosine phosphatase SHP2 in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC); the relationship between tobacco smoking and the expression of SHP2 is also studied...
September 2010: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Chunlan Tang, Xiangdong Zhou, Heping Yang, Qinglian Wang, Rong Zhang
BACKGROUND AND OBJECTIVE: Precious studies proven that aberrant tyrosine phosphorylation has linked with cancer. The aim of this work is to study the expression and significance of SHP2 in non-small cell lung cancer (NSCLC) through tissue microarray technique and immunohistochemical method. METHODS: Eighty NSCLC specimens were constructed into tissue microarray and performed using immunohistochemistry. RESULTS: The total positive rates of SHP2 were 70...
February 2010: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Matthew J Lazzara, Keara Lane, Richard Chan, Paul J Jasper, Michael B Yaffe, Peter K Sorger, Tyler Jacks, Benjamin G Neel, Douglas A Lauffenburger
Most non-small cell lung cancers (NSCLC) display elevated expression of epidermal growth factor receptor (EGFR), but response to EGFR kinase inhibitors is predominantly limited to NSCLC harboring EGFR-activating mutations. These mutations are associated with increased activity of survival pathways, including phosphatidylinositol 3-kinase/AKT and signal transducer and activator of transcription 3/5. We report that EGFR-activating mutations also surprisingly lead to decreased ability to activate extracellular signal-regulated kinase (ERK) compared with wild-type EGFR...
May 1, 2010: Cancer Research
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