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Featured researches published by Yongxin Ren.


Molecular Oncology | 2015

Volitinib, a potent and highly selective c-Met inhibitor, effectively blocks c-Met signaling and growth in c-MET amplified gastric cancer patient-derived tumor xenograft models

Paul R. Gavine; Yongxin Ren; Lu Han; Jing Lv; Shiming Fan; Wei Zhang; Wen Xu; Yuan Jie Liu; Tianwei Zhang; Haihua Fu; Yongjuan Yu; Huiying Wang; Shirlian Xu; Feng Zhou; Xinying Su; Xiaolu Yin; Liang Xie; Linfang Wang; Weiguo Qing; Longxian Jiao; Weiguo Su; Q.May Wang

To investigate the incidence of cMET gene copy number changes and protein overexpression in Chinese gastric cancer (GC) and to preclinically test the hypothesis that the novel, potent and selective cMET small‐molecule inhibitor volitinib, will deliver potent anti‐tumor activity in cMET‐dysregulated GC patient‐derived tumor xenograft (PDX) models.


Journal of Medicinal Chemistry | 2014

Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer.

Hong Jia; Guangxiu Dai; Jianyang Weng; Zhulin Zhang; Qing Wang; Feng Zhou; Longxian Jiao; Yumin Cui; Yongxin Ren; Shiming Fan; Jinghong Zhou; Weiguo Qing; Yi Gu; Jian Wang; Yang Sai; Weiguo Su

HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure-activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.


Cancer Biology & Therapy | 2014

Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy

Qiaoling Sun; Jinghong Zhou; Zheng Zhang; Mingchuan Guo; Junqing Liang; Feng Zhou; Jingwen Long; Wei Zhang; Fang Yin; Huaqing Cai; Haibin Yang; Weihan Zhang; Yi Gu; Liang Ni; Yang Sai; Yumin Cui; Meifang Zhang; Minhua Hong; Junen Sun; Zheng Yang; Weiguo Qing; Weiguo Su; Yongxin Ren

VEGF/VEGFR signal axis has been proven to be an important target for development of novel cancer therapies. One challenging aspect in small molecular VEGFR inhibitors is to achieve sustained target inhibition at tolerable doses previously seen only with the long-acting biologics. It would require high potency (low effective drug concentrations) and sufficient drug exposures at tolerated doses so that the drug concentration can be maintained above effective drug concentration for target inhibition within the dosing period. Fruquintinib (HMPL-013) is a small molecule inhibitor with strong potency and high selectivity against VEGFR family currently in Phase II clinical studies. Analysis of Phase I pharmacokinetic data revealed that at the maximum tolerated dose of once daily oral administration fruquintinib achieved complete VEGFR2 suppression (drug concentrations were maintained above that required to produce >85% inhibition of VEGFR2 phosphorylation in mouse) for 24 hours/day. In this article, the preclinical data for fruquintinib will be described, including kinase enzyme activity and selectivity, cellular VEGFR inhibition and VEGFR-driven functional activity, in vivo VEGFR phosphorylation inhibition in the lung tissue in mouse and tumor growth inhibition in a panel of tumor xenograft and patient derive xenograft models in mouse. Pharmacokinetic and target inhibition data are also presented to provide a correlation between target inhibition and tumor growth inhibition.


Oncotarget | 2016

Acquired savolitinib resistance in non-small cell lung cancer arises via multiple mechanisms that converge on MET-independent mTOR and MYC activation

Ryan Henry; Evan Barry; Lillian Castriotta; Brendon Ladd; Aleksandra Markovets; Garry Beran; Yongxin Ren; Feng Zhou; Ammar Adam; Michael Zinda; Corinne Reimer; Weiguo Qing; Weiguo Su; Edwin Clark; Celina M. D’Cruz; Alwin Schuller

Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. The receptor tyrosine kinase MET has been implicated as an oncogene in numerous cancer subtypes, including non-small cell lung cancer (NSCLC). Here we explore the therapeutic potential of savolitinib (volitinib, AZD6094, HMPL-504), a potent and selective MET inhibitor, in NSCLC. In vitro, savolitinib inhibits MET phosphorylation with nanomolar potency, which correlates with blockade of PI3K/AKT and MAPK signaling as well as MYC down-regulation. In vivo, savolitinib causes inhibition of these pathways and significantly decreases growth of MET-dependent xenografts. To understand resistance mechanisms, we generated savolitinib resistance in MET-amplified NSCLC cell lines and analyzed individual clones. We found that upregulation of MYC and constitutive mTOR pathway activation is a conserved feature of resistant clones that can be overcome by knockdown of MYC or dual mTORC1/2 inhibition. Lastly, we demonstrate that mechanisms of resistance are heterogeneous, arising via a switch to EGFR dependence or by a requirement for PIM signaling. This work demonstrates the efficacy of savolitinib in NSCLC and characterizes acquired resistance, identifying both known and novel mechanisms that may inform combination strategies in the clinic.


Cancer Research | 2011

Abstract 3612: A novel and selective c-Met inhibitor against subcutaneous xenograft and othotopic brain tumor models

Yumin Cui; Guangxiu Dai; Yongxin Ren; Feng Zhou; Shiming Fan; Yang Sai; Yi Gu; James Yan; Jia Li; Weiguo Qing; Weiguo Su

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL HM5016504 is a novel, highly potent and selective c-Met inhibitor under development by HMPL. In preclinical studies, it demonstrated strong in vitro activity against c-Met and its downstream signaling targets, thus blocking the related cellular functions, including proliferation, migration, invasion, scattering and the secretion of VEGF that plays a pivotal role in tumor angiogenesis. The cross-talk between c-Met and EGFR was investigated, and their contribution to downstream signaling cascade was identified in certain tumor cell lines with dysregulation of both c-Met and EGFR. HM5016504 could effectively inhibit the in vivo growth of a number of human tumor xenografts. Particularly, the tumor cells or xengorafts with high fold of c-Met gene amplification showed high sensitivity to HM5016504, such as gastric cancer SNU-5, Hs746T and lung cancer H1993 and EBC-1 cells or their respective xenografts. The compound not only showed activity in subcutaneous xenograft models, but also demonstrated efficacy in an orthotopic brain tumor model induced by U87MG, indicating it could pass blood brain barrier. In vitro and in vivo activities of HM5016504 were found to be closely correlated with the c-Met expression level and activation status. In addition, HM5016504 exhibited a reasonable pharmacokinetic profile and safety window based on the toxicology study results in rats, dogs, and monkeys. The pre-clinical study results suggest that HM5016504 could be a promising c-Met targeting anti-cancer agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3612. doi:10.1158/1538-7445.AM2011-3612


Cancer Research | 2017

Abstract 2089: Evaluation of fruquintinib, a potent and selective oral VEGFR inhibitor, in combination with targeted therapies or immune checkpoint inhibitors in preclinical tumor models

Yongxin Ren; Qiaoling Sun; Jingwen Long; Shiming Fan; Renxiang Tang; Wei Zhang; Xuelei Ge; Jianxing Tang; Linfang Wang; Dongxia Shi; Hongbo Chen; Min Cheng; Weiguo Qing; Weiguo Su

The development of therapies targeting tumor angiogenesis, tumor driver gene alterations and tumor immune evasion has made tremendous advancement in improving overall survival. However, efficacy may be limited and resistance often develops rapidly when targeting a single axis of tumorigenesis. Therefore, it is worthwhile to explore rational combination of therapies based on tumor-specific features. Fruquintinib is a potent and selective oral VEGFR inhibitor currently in Phase III clinical trials for non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). We report here the evaluation of anti-tumor effect of fruquintinib in preclinical animal tumor models in combination with therapies targeting tumor driver gene alterations such as EGFR and c-MET or with immune checkpoints. In NSCLC xenograft models with EGFR activation such as activating mutations, gene amplification or protein overexpression, fruquintinib plus an EGFR tyrosine kinase inhibitor such as gefitinib or theliatinib (HMPL-309) was found to be more efficacious than either monotherapy. For instance, in PC-9 subcutaneous tumor model carrying EGFR exon 19 deletion, single agent treatment with fruquintinib at 2 mg/kg and gefitinib at 5 mg/kg produced the tumor growth inhibition (TGI) of 58% and 63%, respectively, while the combination treatment resulted in a TGI of 100% and tumor regression was observed in 11 of 16 mice treated with combinational therapy. In multiple xenograft models derived from lung cancer or renal cell cancer with c-MET activation (amplification or over-expression), addition of fruquintinib to a c-MET inhibitor savolitinib (AZD6094, HMPL-504) also improved the tumor growth inhibition substantially. At the end of the efficacy studies, CD31 and phosphorylation of EGFR, c-MET, AKT and ERK were analyzed with immunohistochemistry and western blotting method in tumor tissues. The results suggested that the enhanced anti-tumor effect in combination therapy could be attributed to the simultaneous blockade of cell signaling in tumor cells (EGFR or c-MET) and VEGFR suppression in the tumor microenvironment. Up-regulation of the immune inhibitory checkpoints induced by VEGF is one of the important mechanisms for tumor cells to escape immune surveillance. In a syngeneic murine tumor model, co-administration of fruquintinib and anti-PD-L1 antibody was found to provide improved anti-tumor effect compared to fruquintinib or anti-PD-L1 single agent alone. Studies to understand the mechanism responsible for the combination effect are under way. All combinations with fruquintinib described above were well tolerated. The efficacy observed in these models suggested that simultaneous blockade of tumor angiogenesis and tumor cell signaling or immune evasion may be a promising approach in improving treatment outcomes. Citation Format: Yongxin Ren, Qiaoling Sun, Jingwen Long, Shiming Fan, Renxiang Tang, Wei Zhang, Xuelei Ge, Jianxing Tang, Linfang Wang, Dongxia Shi, Hongbo Chen, Min Cheng, Weiguo Qing, Weiguo Su. Evaluation of fruquintinib, a potent and selective oral VEGFR inhibitor, in combination with targeted therapies or immune checkpoint inhibitors in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2089. doi:10.1158/1538-7445.AM2017-2089


Cancer Research | 2013

Abstract 971: Synergistic effect of c-Met inhibitor volitinib in combination with EGFR inhibitor Gefitnib on EGFR-TKI resistant NSCLC model HCC827C4R harboring acquired Met gene amplification.

Feng Zhou; Yongxin Ren; Yumin Cui; Hanyang Chen; Longxian Jiao; Guangxiu Dai; Shiming Fan; Junen Sun; Yongjuan Yu; Yang Sai; Yi Gu; Weiguo Qing; Weiguo Su

It is well recognized that non-small cell lung carcinoma (NSCLC) patients with activating EGFR mutations will develop drug resistance after receiving EGFR-tyrosine kinase inhibitors (EGFR-TKI). About 20% of those patients with TKI resistance were identified to harbor Met gene amplification. The aim of this study includes two aspects: a) generating an acquired c-Met amplified EGFR-TKI resistant tumor line in preclinical setting, and b) exploring combination effect of c-met inhibitor volitinib and EGFR inhibitor gefitinib on the new tumor line. Volitinib is a novel, highly potent and selective c-Met inhibitor, currently being evaluated in the phase I clinical trial. HCC827(exon 19 del E746-A750), a human NSCLC cell line, was treated with increasing concentrations of EGFR inhibitor for about 6 months and gradually produced the resistance to EGFR-TKIs, such as gefitinib and erlotinib. One of the subclones, HCC827C4R was isolated and was confirmed to carry Met gene amplification in comparison to parent cell line HCC827. It was not sensitive to volitinib treatment in cell survival assay due to dual activation of EGFR and c-Met pathways. The results from signal pathway study demonstrated that in HCC827C4R cells, volitinib or gefitinib alone only inhibited the phosphorylation of c-Met or EGFR, respectively, but had no effect on the activation of downstream molecules such as Akt and ERK which drive tumor cell proliferation and other cell functions. In contrast, combination of volitinib and gefitinib significantly inhibited phosphorylation of EGFR, c-Met, Akt and ERK in HCC827C4R, and consequently led to a synergistic effect on inhibiting tumor cell growth in vitro. These results were further confirmed in HCC827C4R xenograft model in vivo at clinically relevant doses. Combination of volitinib and gefitinib induced significant tumor regression and displayed synergistic effect compared to treatment by either gefitinib or volitinib alone. Consistent with in vitro results, combination group strongly inhibited the downstream Akt and ERK phosphorylation. In addition, combination treatment was well tolerant and no significant drug-drug exposure interaction was observed. These data indicated that both c-Met and EGFR could contribute to activating downstream signaling pathway and control HCC827C4R cell growth. Blocking either pathway may not be strong enough to stop tumor growth. In conclusion, a cell line with activating EGFR mutation and c-Met gene amplification was generated with resistance to gefitinib and insensitivity to volitinib. The combination treatment with volitinib and an EGFR inhibitor gefitinib was highly effective in vitro and in vivo, suggesting that such combination could provide a safe and effective treatment in clinics for this particular patient population. Citation Format: Feng Zhou, Yongxin Ren, Yumin Cui, Hanyang Chen, Longxian Jiao, Guangxiu Dai, Shiming Fan, Junen Sun, Yongjuan Yu, Yang Sai, Yi Gu, Weiguo Qing, Weiguo Su. Synergistic effect of c-Met inhibitor volitinib in combination with EGFR inhibitor Gefitnib on EGFR-TKI resistant NSCLC model HCC827C4R harboring acquired Met gene amplification. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 971. doi:10.1158/1538-7445.AM2013-971


Oncotarget | 2017

Anti-tumor efficacy of theliatinib in esophageal cancer patient-derived xenografts models with epidermal growth factor receptor (EGFR) overexpression and gene amplification

Yongxin Ren; Jianming Zheng; Shiming Fan; Linfang Wang; Min Cheng; Dongxia Shi; Wei Zhang; Renxiang Tang; Ying Yu; Longxian Jiao; Jun Ni; Haibin Yang; Huaqing Cai; Fang Yin; Yunxin Chen; Feng Zhou; Weihan Zhang; Weiguo Qing; Weiguo Su

Targeted therapy is not yet approved for esophageal cancer (EC). In this study, we first evaluated EGFR gene and protein expression in 70 Chinese EC patient tumor samples collected during surgery. We then established 23 patient-derived EC xenograft (PDECX) models and assessed the efficacy of theliatinib, a potent and highly selective EGFR inhibitor currently in Phase I clinical study, in 9 PDECX models exhibiting various EGFR expression levels. Immunohistochemical analysis showed that 50 patient tumor samples (71.4%) had high EGFR expression. Quantitative PCR showed that eight tumors (11.6%) had EGFR gene copy number gain, and fluorescence in situ hybridization (FISH) revealed that four tumors had EGFR gene amplification. These results suggest that EGFR protein may be overexpressed in many EC tumors without gene amplification. Also detected were rare hot-spot mutations in EGFR and PIK3CA, whereas no mutations were found in K-Ras or B-Raf. Theliatinib exhibited strong antitumor activity in PDECX models with high EGFR expression, including remarkable tumor regression in two PDECX models with both EGFR gene amplification and protein overexpression. However, the efficacy of theliatinib was diminished in models with PI3KCA mutations or FGFR1 overexpression in addition to high EGFR expression. This study demonstrates that theliatinib could potentially benefit EC patients with high EGFR protein expression without mutations or aberrant activities of associated factors, such as PI3KCA or FGFR1.Targeted therapy is not yet approved for esophageal cancer (EC). In this study, we first evaluated EGFR gene and protein expression in 70 Chinese EC patient tumor samples collected during surgery. We then established 23 patient-derived EC xenograft (PDECX) models and assessed the efficacy of theliatinib, a potent and highly selective EGFR inhibitor currently in Phase I clinical study, in 9 PDECX models exhibiting various EGFR expression levels. Immunohistochemical analysis showed that 50 patient tumor samples (71.4%) had high EGFR expression. Quantitative PCR showed that eight tumors (11.6%) had EGFR gene copy number gain, and fluorescence in situ hybridization (FISH) revealed that four tumors had EGFR gene amplification. These results suggest that EGFR protein may be overexpressed in many EC tumors without gene amplification. Also detected were rare hot-spot mutations in EGFR and PIK3CA, whereas no mutations were found in K-Ras or B-Raf. Theliatinib exhibited strong antitumor activity in PDECX models with high EGFR expression, including remarkable tumor regression in two PDECX models with both EGFR gene amplification and protein overexpression. However, the efficacy of theliatinib was diminished in models with PI3KCA mutations or FGFR1 overexpression in addition to high EGFR expression. This study demonstrates that theliatinib could potentially benefit EC patients with high EGFR protein expression without mutations or aberrant activities of associated factors, such as PI3KCA or FGFR1.


Molecular Cancer Therapeutics | 2015

Abstract B189: Synergistic effect of c-Met inhibitor savolitinib in combination with a VEGFR inhibitor fruquintinib in clear cell renal cell carcinoma xenograft models

Yongxin Ren; Shiming Fan; Yunxin Chen; Renxiang Tang; Wei Zhang; Jianxing Tang; Linfang Wang; Dongxia Shi; Hongbo Chen; Min Cheng; Weiguo Qing; Weiguo Su

Renal cell carcinoma (RCC) is the most common type of kidney tumor in human. Approximately 80∼85% of RCC is clear cell renal cell carcinoma (ccRCC). [1] Although VEGF/VEGFR targeted therapies bring significant advances in the treatment of RCC, ultimate resistance occurs in most cases following a transient period of clinical benefit. [2] The hepatocyte growth factor (HGF) receptor c-Met activation emerges as one of the mechanisms for resistance to anti-VEGF/VEGFR therapies in ccRCC, [3] implying that a combinational inhibition of c-Met and VEGFR pathways may induce a synergistic anti-tumor effect and could produce additional clinical benefit. The aim of this study was to assess the effect of a combination strategy targeting the VEGFR and c-Met pathways in ccRCC xenograft models. Savolitinib (AZD6094, HMPL-504) is a highly selective inhibitor against c-Met. Fruquintinib (HMPL-013) strongly inhibits VEGFR1, 2 and 3. Both of them were discovered by Hutchison MediPharma and are currently being evaluated in clinical trials for the treatment of various cancers. Several subcutaneous xenograft models were established in nude mice with human ccRCC cell lines or patient derived tumors (PDX) to investigate the anti-tumor effect of combination of savolitinib with fruquntinib. Treatment with savolitinib or fruquintinib at clinically relevant dose only exhibited mild to moderate tumor growth inhibition as a single agent in all of tested models, but significantly increased anti-tumor effect was observed in all of tested models for the combination group. It seemed that the enhanced anti-tumor effect was associated with c-Met inhibition. In a ccRCC PDX model KIN1T1342, the increased anti-tumor effect was correlated with dose increment of savolitinib. Immunohistochemistry (IHC) analysis revealed that combination treatment produced stronger inhibition on tumor proliferation marker Ki67 and angiogenesis marker CD31, compared to either savolitinib or fruquntinib alone, indicating that the observed synergistic effect might be attributed to the dual inhibition on tumor signaling and tumor microenvironment. C-Met expression was observed in all tested models, and treatment with savolitinib effectively suppressed phospho-Met. To evaluate c-Met expression in Chinese ccRCC patients, Formalin-Fixed and Parrffin-Embedded (FFPE) tumor sections were collected from sixty-two treatment-naive patients during surgical resection. Positive c-Met expression was found in 69% (43/62) of ccRCC samples under IHC staining.Overall our data demonstrated that c-Met was widely expressed in Chinese ccRCC patients and provided a rationale to test the combined HGF/c-Met and VEGF/VEGFR pathway blockade in the treatment of ccRCC in the clinical trials. References: 1. Harshman LC et al . Cancer J. 2013;19: 316-323 2. Swanton C et al . Genome Med. 2010; 2(8): 53 3.Ciamporcero E et al . Mol Cancer Ther. 2015: 14 (1); 101-10. Citation Format: Yongxin Ren, Shiming Fan, Yunxin Chen, Renxiang Tang, Wei Zhang, Jianxing Tang, Linfang Wang, Dongxia Shi, Hongbo Chen, Min Cheng, Weiguo Qing, Weiguo Su. Synergistic effect of c-Met inhibitor savolitinib in combination with a VEGFR inhibitor fruquintinib in clear cell renal cell carcinoma xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B189.


Molecular Cancer Therapeutics | 2015

Abstract LB-C22: Acquired resistance to the cMET inhibitor savolitinib in lung cancer models through EGFR/mTOR/MYC deregulation and adoption of PIM signaling

Ryan Henry; Evan Barry; Brendon Ladd; Aleksandra Markovets; Garry Beran; Yongxin Ren; Feng Zhou; Lillian Castriotta; Ammar Adam; Weiguo Qing; Weiguo Su; Edwin Clark; Celina D'Cruz; Alwin Schuller

Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. Aberrant receptor tyrosine kinase (RTK) signaling is a well-documented driver of disease onset and progression in multiple cancer types, including non-small cell lung cancer (NSCLC), where the cMET RTK contributes to tumor progression, maintenance and resistance to targeted therapies. Here, we explore the therapeutic potential of the potent and selective cMET inhibitor savolitinib (volitinib, AZD6094, HMPL-504) in NSCLC and begin to elucidate mechanisms of acquired savolitinib resistance in preclinical models. Using in vitro proliferation assays and immunoblot analysis, we determine that savolitinib rapidly inhibits cMET auto-phosphorylation/activation and reduces the viability of NSCLC cell lines NCI-H1993 and EBC-1 with a GI50 of 4.20 nM and 2.14 nM, respectively. In vivo, once daily treatment of NCI-H1993 xenografts with 3.0 mg/kg savolitinib significantly slows tumor growth, whereas treatment of EBC-1 xenografts with 30.0 mg/kg results in tumor stasis. Importantly, we observe tumor regressions in a patient-derived xenograft model of a NSCLC lymph node metastasis, HLXF-036LN, dosed with savolitinib 50.0 mg/kg once daily. Pharmacodynamic analysis of in vitro and in vivo models shows that savolitinib sensitivity correlates with blockade of PI3K/AKT and MAPK signaling, and interestingly, with cMYC (MYC) protein down-regulation. To elucidate mechanisms of acquired resistance in NSCLC, we generated savolitinib resistance in vitro using the NCI-H1993 and EBC-1 cell lines and further sub-cloned resistant NCI-H1993 cells to study the heterogeneity of resistance mechanisms. Using small-molecule screening, phospho-protein arrays and interrogation of signaling pathway activity by immunoblot, we identify 1) deregulated mTORC1/2 signaling and 2) the uncoupling of MYC expression from cMET activation as commonly contributing to resistance in all clones tested. RNA interference (siRNA) and MYC over-expression experiments confirm the novel finding that sustained MYC expression can partially drive resistance to a tyrosine kinase inhibitor such as savolitinib. Additionally, we identify clone-specific resistance mechanisms arising via a previously-described switch to EGFR dependence or by our novel finding of a de novo requirement for PIM signaling. Taken together, this work demonstrates the preclinical efficacy of savolitinib in NSCLC and provides an initial characterization of potential resistance mechanisms, identifying core resistance targets and clone-specific vulnerabilities that could be exploited to counter acquired savolitinib resistance that may emerge in the clinic. Citation Format: Ryan E. Henry, Evan R. Barry, Brendon Ladd, Aleksandra Markovets, Garry J. Beran, Yongxin Ren, Feng Zhou, Lillian Castriotta, Ammar Adam, Weiguo Qing, Weiguo Su, Edwin Clark, Celina M. D9Cruz, Alwin Schuller. Acquired resistance to the cMET inhibitor savolitinib in lung cancer models through EGFR/mTOR/MYC deregulation and adoption of PIM signaling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C22.

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Jianming Zheng

Second Military Medical University

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Wei Zhang

Center for Advanced Materials

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