P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer

Katayama, Ryohei; Sakashita, Takuya; Yanagitani, Noriko; Ninomiya, Hironori; Horiike, Atsushi; Friboulet, Luc; Gainor, Justin F.; Motoi, Noriko; Dobashi, Akito; Sakata, Seiji; Tambo, Yuichi; Kitazono, Satoru; Sato, Shigeo; Koike, Sumie; Iafrate, A. John; Mino‐Kenudson, Mari; Ishikawa, Yuichi; Shaw, Alice T.; Engelman, Jeffrey A.; Takeuchi, Kengo; Nishio, Makoto; Fujita, Naoya

doi:10.1016/j.ebiom.2015.12.009

Cited by 128 publications

(108 citation statements)

References 41 publications

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“…Recent work has identified P-gp overexpression as a potential resistance mechanism in 3 of 11 ALK -positive, crizotinib- or ceritinib-resistant NSCLC patients (105). In a patient-derived cell line overexpressing P-gp, shRNA-mediated knockdown of ABCB1 or pharmacologic inhibition of P-gp using verapamil re-sensitized the resistant cells to crizotinib and ceritinib (105). These findings need to be validated in larger patient cohorts.…”

Section: Mechanisms Of Resistance To Alk Tkismentioning

confidence: 99%

Targeting ALK: Precision Medicine Takes on Drug Resistance

2017

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Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, including non-small-cell lung cancer (NSCLC). However, the clinical benefit of targeting ALK using tyrosine kinase inhibitors (TKIs) is almost universally limited by the emergence of drug resistance. Diverse mechanisms of resistance to ALK TKIs have now been discovered, and these basic mechanisms are informing the development of novel therapeutic strategies to overcome resistance in the clinic. In this Review, we summarize the current successes and challenges of targeting ALK.

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Section: Mechanisms Of Resistance To Alk Tkismentioning

confidence: 99%

Targeting ALK: Precision Medicine Takes on Drug Resistance

2017

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“…However, despite the efficacy of second-generation ALK inhibitors, patients almost invariably relapse. Thus far, descriptions of molecular mechanisms of resistance to second-generation ALK inhibitors have been limited to in vitro studies, case reports and small clinical series, making it difficult to determine the scope of such alterations (17, 19–23). …”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors inALK-Rearranged Lung Cancer

et al. 2016

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Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib, alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation - ALK G1202R - increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.

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“…Using TrkAi as a monotherapy or combined with low concentrations of CHOP hindered the growth of the lymphoma tumors in vivo and improved mice survival. Although selective ALK inhibitors represent an emerging strategy to treat ALK + neoplasms including NPM‐ALK + T‐cell lymphoma (Mosse et al ., 2013), several resistance mechanisms to these inhibitors have been already identified and characterized, which represents an important limitation (Dong et al ., 2016; Isozaki et al ., 2016; Katayama et al ., 2016; Zdzalik et al ., 2014). Our findings suggest that TrkA inhibition could represent an alternative therapeutic approach to tackle this aggressive neoplasm.…”

Section: Discussionmentioning

confidence: 99%

TrkA is a binding partner of NPM‐ALK that promotes the survival of ALK⁺ T‐cell lymphoma

Shi

George

et al. 2017

Molecular Oncology

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Nucleophosmin‐anaplastic lymphoma kinase‐expressing (NPM‐ALK +) T‐cell lymphoma is an aggressive neoplasm that is more commonly seen in children and young adults. The pathogenesis of NPM‐ALK + T‐cell lymphoma is not completely understood. Wild‐type ALK is a receptor tyrosine kinase that is physiologically expressed in neural tissues during early stages of human development, which suggests that ALK may interact with neurotrophic factors. The aberrant expression of NPM‐ALK results from a translocation between the ALK gene on chromosome 2p23 and the NPM gene on chromosome 5q35. The nerve growth factor (NGF) is the first neurotrophic factor attributed to non‐neural functions including cancer cell survival, proliferation, and metastasis. These functions are primarily mediated through the tropomyosin receptor kinase A (TrkA). The expression and role of NGF/TrkA in NPM‐ALK + T‐cell lymphoma are not known. In this study, we tested the hypothesis that TrkA signaling is upregulated and sustains the survival of this lymphoma. Our data illustrate that TrkA and NGF are expressed in five NPM‐ALK + T‐cell lymphoma cell lines and TrkA is expressed in 11 of 13 primary lymphoma tumors from patients. In addition, we found evidence to support that NPM‐ALK and TrkA functionally interact. A selective TrkA inhibitor induced apoptosis and decreased cell viability, proliferation, and colony formation of NPM‐ALK + T‐cell lymphoma cell lines. These effects were associated with downregulation of cell survival regulatory proteins. Similar results were also observed using specific knockdown of TrkA in NPM‐ALK + T‐cell lymphoma cells by siRNA. Importantly, the inhibition of TrkA signaling was associated with antitumor effects in vivo, because tumor xenografts in mice regressed and the mice exhibited improved survival. In conclusion, TrkA plays an important role in the pathogenesis of NPM‐ALK + T‐cell lymphoma, and therefore, targeting TrkA signaling may represent a novel approach to eradicate this aggressive neoplasm.

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P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer

Cited by 128 publications

References 41 publications

Targeting ALK: Precision Medicine Takes on Drug Resistance

Targeting ALK: Precision Medicine Takes on Drug Resistance

Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors inALK-Rearranged Lung Cancer

TrkA is a binding partner of NPM‐ALK that promotes the survival of ALK⁺ T‐cell lymphoma

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P-glycoprotein Mediates Ceritinib Resistance in Anaplastic Lymphoma Kinase-rearranged Non-small Cell Lung Cancer

Cited by 128 publications

References 41 publications

Targeting ALK: Precision Medicine Takes on Drug Resistance

Targeting ALK: Precision Medicine Takes on Drug Resistance

Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors inALK-Rearranged Lung Cancer

TrkA is a binding partner of NPM‐ALK that promotes the survival of ALK+ T‐cell lymphoma

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TrkA is a binding partner of NPM‐ALK that promotes the survival of ALK⁺ T‐cell lymphoma