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Alternative Signaling Pathways as Potential Therapeutic Targets for Overcoming EGFR and c-Met Inhibitor Resistance in Non-Small Cell Lung Cancer  [PDF]
Jason T. Fong, Ryan J. Jacobs, David N. Moravec, Srijayaprakash B. Uppada, Gregory M. Botting, Marie Nlend, Neelu Puri
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078398
Abstract: The use of tyrosine kinase inhibitors (TKIs) against EGFR/c-Met in non-small cell lung cancer (NSCLC) has been shown to be effective in increasing patient progression free survival (PFS), but their efficacy is limited due to the development of resistance and tumor recurrence. Therefore, understanding the molecular mechanisms underlying development of drug resistance in NSCLC is necessary for developing novel and effective therapeutic approaches to improve patient outcome. This study aims to understand the mechanism of EGFR/c-Met tyrosine kinase inhibitor (TKI) resistance in NSCLC. H2170 and H358 cell lines were made resistant to SU11274, a c-Met inhibitor, and erlotinib, an EGFR inhibitor, through step-wise increases in TKI exposure. The IC50 concentrations of resistant lines exhibited a 4–5 and 11–22-fold increase for SU11274 and erlotinib, respectively, when compared to parental lines. Furthermore, mTOR and Wnt signaling was studied in both cell lines to determine their roles in mediating TKI resistance. We observed a 2–4-fold upregulation of mTOR signaling proteins and a 2- to 8-fold upregulation of Wnt signaling proteins in H2170 erlotinib and SU11274 resistant cells. H2170 and H358 cells were further treated with the mTOR inhibitor everolimus and the Wnt inhibitor XAV939. H358 resistant cells were inhibited by 95% by a triple combination of everolimus, erlotinib and SU11274 in comparison to 34% by a double combination of these drugs. Parental H2170 cells displayed no sensitivity to XAV939, while resistant cells were significantly inhibited (39%) by XAV939 as a single agent, as well as in combination with SU11274 and erlotinib. Similar results were obtained with H358 resistant cells. This study suggests a novel molecular mechanism of drug resistance in lung cancer.
Meis1 Is Required for c-Met Inhibition to Suppress Cell Proliferation of Skin Squamous Cell Carcinoma Cells  [PDF]
Megumi Saito, Kazuhiro Okumura, Yasuhiro Yoshizawa, Haruka Munakata, Eriko Isogai, Yuichi Wakabayashi
Journal of Biosciences and Medicines (JBM) , 2016, DOI: 10.4236/jbm.2016.47007
Abstract: Previous studies have shown that Meis1 plays an important role in the pathogenesis of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Meis1 belongs to the TALE family, the members of which are used as biomarkers for AML. Meis1 has been shown to play a functional role in epithelial tissues, such as skin. However, its functions in skin carcinogenesis remain poorly understood. On the other hand, the c-Met inhibitor SU11274 has been identified through drug screening with HOXA9/Meis1-induced AML cell lines. SU11274 altered cell proliferation and the cell cycle status in human AML cell lines. Thus, we hypothesized that the effects of SU11274 are dependent on Meis1 and that its knockdown may diminish the effects of SU11274 not only in AML cell lines, but also in skin cancer cell lines. In order to test our hypothesis, we established Meis1 knockdown cell lines using two skin squamous cell carcinoma cell lines (B9 and D3) and treated these cell lines with SU11274. The results obtained showed that SU11274 suppressed cell proliferation by modulating cell cycle progression in the presence of Meis1, but not in its absence. Furthermore, an expression analysis showed that SU11274 activated the transcription of Meis1, which led to the transcription of Hif1α and Cdkn2a (p16Ink4a and p19Arf). These results suggest that Meis1 is required for the c-Met inhibitor SU11274 to suppress the proliferation of the skin squamous cell carcinoma cell lines.
Inhibition of rhabdomyosarcoma's metastatic behavior through downregulation of MET receptor signaling.  [cached]
Ewa Lukasiewicz,Katarzyna Miekus,Jacek Kijowski,Grazyna Drabik
Folia Histochemica et Cytobiologica , 2010, DOI: 10.5603/4331
Abstract: Rhabdomyosarcoma (RMS) is a soft tissue sarcoma usually diagnosed in children. In advanced and metastatic stages the prognosis is often poor. RMS cell lines were used for evaluation of the role of MET receptor inhibition on chemotaxis and invasion. In vivo studies were performed using NOD-SCID xenograft model. This study shows that blocking of MET expression has strong influence on metastatic behavior of RMS. MET negative cells possess a reduced potential to migrate and to invade. Downregulation of MET suppressed the ability of RMS cells to populate bone marrow. Inhibition of MET negative tumor cells engraftment into bone marrow was observed. MET negative tumors were also two to four times smaller than their wild type counterparts. Since MET receptor plays a very important role in facilitating metastasis of RMS cells, blocking of HGF-MET axis might be considered as a therapeutic option for RMS patients, at more advanced and metastatic stages.
SU11274逆转肝细胞生长因子诱导不同EGFR基因型非小细胞肺癌细胞株对吉非替尼耐药
SU11274 reverse gefitinib resistance induced by hepatocyte growth factor in different EGFR gene type of non-small cell lung cancer cells  [PDF]
严春花,玄香兰,张佳,等
YAN Chunhua, XUAN Xianglan, ZHANG Jia, et al
- , 2015, DOI: 10.3969/j.issn.1007-3969.2015.02.004
Abstract: 　 背景与目的：肝细胞生长因子(hepatocyte growth factor，HGF)诱导敏感非小细胞肺癌(nonsmall cell lung cancer，NSCLC)细胞对表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor，EGFR-TKI)耐药，其机制与c-Met激活有关。本研究探讨c-Met抑制剂SU11274逆转HGF诱导的不同EGFR基因型NSCLC细胞株对吉非替尼耐药及逆转耐药机制。方法：选择人NSCLC细胞株PC9(EGFR突变型)、H292(EGFR野生型)和A549(EGFR野生型)，应用吉非替尼和SU11274单独或联合作用于HGF诱导的细胞株。实验分为6组：C组(不加药对照组)、H组(HGF处理组)、G组(吉非替尼处理组)、S(SU11274处理组)、HG组(HGF+吉非替尼处理组)和HGS组(HGF+吉非替尼+SU11274处理组)。MTT法检测对细胞增殖的影响，流式细胞术检测细胞凋亡的影响；应用蛋白质印迹法(Western blot)检测细胞中c-Met及其下游通道Stat3、Akt和Erk1/2蛋白表达水平。结果：吉非替尼对3种细胞的生长抑制作用均呈浓度依赖性，HGF处理能够缓解吉非替尼的增殖抑制作用(P<0.05)；不同浓度吉非替尼联合SU11274作用于HGF诱导细胞时，3种细胞株存活率比吉非替尼单独作用于HGF诱导细胞时明显降低(P<0.05)；HGS组的细胞凋亡比HG组明显增加(P<0.05)；HGS组的c-Met、Stat3、Akt和Erk1/2活化蛋白量比HG组明显减少。结论：c-Met抑制剂SU11274可逆转HGF诱导的不同EGFR基因型NSCLC细胞株对吉非替尼耐药，其机制可能与抑制HGF活化的c-Met及其下游通道蛋白表达有关。
Low Dose Histone Deacetylase Inhibitor, Depsipeptide (FR901228), Promotes Adenoviral Transduction in Human Rhabdomyosarcoma Cell Lines  [PDF]
Fariba Navid,Blaine T. Mischen,Lee J. Helman
Sarcoma , 2004, DOI: 10.1080/13577140410001679220
Abstract: Purpose. Transduction of rhabdomyosarcoma (RMS) cells with adenoviral vectors for in vivo and in vitro applications has been limited by the low to absent levels of coxackie and adenovirus receptor (CAR). This study investigates the potential use of low doses of a histone deacetylase inhibitor, depsipeptide (FR901228), currently in Phase II human trials, to enhance adenoviral uptake in six rhabdomyosarcoma cell lines.
Targeting Wild-Type and Mutationally Activated FGFR4 in Rhabdomyosarcoma with the Inhibitor Ponatinib (AP24534)  [PDF]
Samuel Q. Li, Adam T. Cheuk, Jack F. Shern, Young K. Song, Laura Hurd, Hongling Liao, Jun S. Wei, Javed Khan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076551
Abstract: Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway.
Synergistic Effect of Afatinib with Su11274 in Non-Small Cell Lung Cancer Cells Resistant to Gefitinib or Erlotinib  [PDF]
Gang Chen, Alfiah Noor, Peter Kronenberger, Erik Teugels, Ijeoma Adaku Umelo, Jacques De Grève
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059708
Abstract: Epidermal growth factor receptor (EGFR) and c-MET receptors are expressed on many non-small cell lung cancer (NSCLC) cells. Current single agent therapeutic targeting of a mutant EGFR has a high efficacy in the clinic, but is not curative. Here, we investigated the combination of targeting EGFR and c-MET pathways in NSCLC cells resistant to receptor tyrosine kinase inhibitors (TKIs), using RNA interference and inhibition by TKIs. Different NSCLC cell lines with various genomic characteristics (H358, H1650 and H1975) were transfected with EGFR-specific-siRNA, T790M-specific-siRNA, c-MET siRNA or the combination. Subsequently EGFR TKIs (gefitinib, erlotinib or afatinib) or monoclonal antibody cetuximab were combined respectively with the c-MET-specific TKI su11274 in NSCLC cell lines. The cell proliferation, viability, caspase？3/7 activity and apoptotic morphology were monitored by spectrophotometry, fluorimetry and fluorescence microscopy. The combined effect of EGFR TKIs, or cetuximab and su11274, was evaluated using a combination index. The results showed that the cell lines that were relatively resistant to EGFR TKIs, especially the H1975 cell line containing the resistance T790M mutation, were found to be more sensitive to EGFR-specific-siRNA. The combination of EGFR siRNA plus c-MET siRNA enhanced cell growth inhibition, apoptosis induction and inhibition of downstream signaling in EGFR TKI resistant H358, H1650 and H1975 cells, despite the absence of activity of the c-MET siRNA alone. EGFR TKIs or cetuximab plus su11274 were also consistently superior to either agent alone. The strongest biological effect was observed when afatinib, an irreversible pan-HER blocker was combined with su11274, which achieved a synergistic effect in the T790M mutant H1975 cells. In a conclusion, our findings offer preclinical proof of principle for combined inhibition as a promising treatment strategy for NSCLC, especially for patients in whom current EGFR-targeted treatments fail due to the presence of the T790M-EGFR-mutation or high c-MET expression.
Efficacy of c-Met inhibitor for advanced prostate cancer
William H Tu, Chunfang Zhu, Curtis Clark, James G Christensen, Zijie Sun
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-556
Abstract: We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression.We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration.The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer.Prostate cancer is the most common malignancy in men in the United States [1]. While the mortality of prostate cancer has been slightly reduced recently, it still contributes to 30,000 deaths annually with the majority from castration resistant prostate cancer (CRPC) [2]. The androgen-signaling pathway, mediated mostly through the androgen receptor (AR), plays a critical role in the regulation of prostate cancer cell growth and survival [3,4]. Androgen deprivation is the standard therapy for advanced prostate cancer [5]. However, within two to three years after initiating therapy, most patients relapse with a more aggressive form of prostate cancer, termed CRPC, for which there is no effective treatment.The c-Met receptor tyrosine kinase (RTK) was originally discovered as an oncoprotein and has been implicated in the proliferation and progression of a wide variety of human malignancies, including prostate cancer [6-9]. High c-Met expression is observed in late stages and metastases
Phosphocaveolin-1 Enforces Tumor Growth and Chemoresistance in Rhabdomyosarcoma  [PDF]
Fiorella Faggi, Stefania Mitola, Guglielmo Sorci, Francesca Riuzzi, Rosario Donato, Silvia Codenotti, Pietro Luigi Poliani, Manuela Cominelli, Raffaella Vescovi, Stefania Rossi, Stefano Calza, Marina Colombi, Fabio Penna, Paola Costelli, Ilaria Perini, Maurilio Sampaolesi, Eugenio Monti, Alessandro Fanzani
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0084618
Abstract: Caveolin-1 (Cav-1) can ambiguously behave as either tumor suppressor or oncogene depending on its phosphorylation state and the type of cancer. In this study we show that Cav-1 was phosphorylated on tyrosine 14 (pCav-1) by Src-kinase family members in various human cell lines and primary mouse cultures of rhabdomyosarcoma (RMS), the most frequent soft-tissue sarcoma affecting childhood. Cav-1 overexpression in the human embryonal RD or alveolar RH30 cells yielded increased pCav-1 levels and reinforced the phosphorylation state of either ERK or AKT kinase, respectively, in turn enhancing in vitro cell proliferation, migration, invasiveness and chemoresistance. In contrast, reducing the pCav-1 levels by administration of a Src-kinase inhibitor or through targeted Cav-1 silencing counteracted the malignant in vitro phenotype of RMS cells. Consistent with these results, xenotransplantation of Cav-1 overexpressing RD cells into nude mice resulted in substantial tumor growth in comparison to control cells. Taken together, these data point to pCav-1 as an important and therapeutically valuable target for overcoming the progression and multidrug resistance of RMS.
Greatwall-phosphorylated Endosulfine is Both an Inhibitor and a Substrate of PP2A-B55 Heterotrimers  [PDF]
Byron C. Williams,Joshua J. Filter,Kristina A. Blake-Hodek,Brian E. Wadzinski,Nicholas J. Fuda,David Shalloway,Michael L. Goldberg
Quantitative Biology , 2014,
Abstract: During M phase, Endosulfine (Endos) family proteins are phosphorylated by Greatwall kinase (Gwl), and the resultant pEndos inhibits the phosphatase PP2A-B55, which would otherwise prematurely reverse many CDK-driven phosphorylations. We show here that PP2A-B55 is the enzyme responsible for dephosphorylating pEndos during M phase exit. The kinetic parameters for PP2A-B55's action on pEndos are orders of magnitude lower than those for CDK-phosphorylated substrates, suggesting a simple model for PP2A-B55 regulation that we call inhibition by unfair competition. As the name suggests, during M phase PP2A-B55's attention is diverted to pEndos, which binds much more avidly and is dephosphorylated more slowly than other substrates. When Gwl is inactivated during the M phase-to-interphase transition, the dynamic balance changes: pEndos dephosphorylated by PP2A-B55 cannot be replaced, so the phosphatase can refocus its attention on CDK-phosphorylated substrates. This mechanism explains simultaneously how PP2A-B55 and Gwl together regulate pEndos, and how pEndos controls PP2A-B55.
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