Non–Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases

Isozaki, Hideko; Ichihara, Eiki; Takigawa, Nagio; Ohashi, Kadoaki; Ochi, Nobuaki; Yasugi, Masayuki; Ninomiya, Takashi; Yamane, Hiromichi; Hotta, Katsuyuki; Sakai, Katsuya; Matsumoto, Kunio; Hosokawa, Shinobu; Bessho, Akihiro; Sendo, Toshiaki; Tanimoto, Mitsune; Kiura, Katsuyuki

doi:10.1158/0008-5472.can-15-1010

Cited by 116 publications

(86 citation statements)

References 39 publications

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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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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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“…As explained for brigatinib, its double activity upon ALK and EGFR signaling could be useful when the second is involved in resistance mechanisms. The recently reported activation of c-MET, HER-3 and IGF-1R pathways in alectinib-resistant ALK-rearranged cells lines rise the issue of combined molecular treatments addressing to tumor-tailored biologic alterations (117). The latter concept has already been approached in in vitro pharmacological screens (118) and could be applicable in ALK-positive tumors where KRAS activation is the putative responsible of treatment resistance and clinical progression, with the putative double blockade (ALK and MEK inhibition) in a melanomaoriented fashion.…”

Section: Positioning In Clinical Practicementioning

confidence: 99%

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Facchinetti¹,

Tiseo²,

Maïo³

et al. 2016

Transl. Lung Cancer Res.

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Abstract:Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/ RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient.

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“…Because of their benefits over other therapies, ALK tyrosine kinase inhibitors (ALK TKIs) are used as the chemotherapeutic agents of choice in NSCLC with ALK rearrangement (6). However, most cases receiving ALK inhibitors relapse within a few years after starting therapy (7)(8)(9)(10). Ongoing research mainly attempts to develop new small molecule inhibitors with greater potency against ALK and activity against acquired mutations (11).…”

Section: Introductionmentioning

confidence: 99%

“…Ongoing research mainly attempts to develop new small molecule inhibitors with greater potency against ALK and activity against acquired mutations (11). Unfortunately, the second and third generation ALK inhibitors also show failure (8,12). Several studies have suggested that the combination of two or more therapeutic treatments is more effective than treatment with ALK TKI alone.…”

Section: Introductionmentioning

confidence: 99%

Integrin β3 Inhibition Enhances the Antitumor Activity of ALK Inhibitor in ALK-Rearranged NSCLC

Noh

Sohn

Song

et al. 2018

Clinical Cancer Research

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Purpose: Anaplastic lymphoma kinase (ALK)-positive cancers are sensitive to small-molecule ALK kinase inhibitors, but most cases experience failure following treatment. Hence, additional drug targets and combination therapeutic treatments are needed. We investigated gene expression that is regulated by the expression of ALK and explored its roles in cancer progression and therapeutic implication. Experimental Design: We screened ALK-rearranged non–small cell lung cancer (NSCLC) cases using immunohistochemistry and fluorescence in situ hybridization and then conducted multiplex gene expression analysis. We also performed a clinicopathologic analysis to validate the findings. Additional cellular experiments, including inhibition and migration assays, and in vivo lung cancer model studies were performed. Results: Among patients with ALK-rearranged NSCLC, integrin β3 (ITGB3) was one of the overexpressed genes in comparison with that in ALK-negative NSCLC (P = 0.0003). ALK and integrin β3 expression were positively correlated, and we discovered that high integrin β3 mRNA expression was associated with metastasis and more advanced tumor stages (P < 0.005; P < 0.05). Furthermore, we found that inhibition of both ALK and integrin β3 led to increased drug sensitivity in vitro and in vivo (both P < 0.05). Conclusions: We discovered a positive correlation between ALK and integrin β3 expression levels in ALK-rearranged NSCLC. Our findings suggest that high integrin β3 expression in ALK-rearranged NSCLC is associated with tumor progression and a worse prognosis. This finding demonstrates the prognostic value of integrin β3 and provides a rationale for combination treatment with ALK and integrin β3 inhibitors in patients with ALK-rearranged NSCLC. Clin Cancer Res; 24(17); 4162–74. ©2018 AACR.

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Non–Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases

Cited by 116 publications

References 39 publications

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

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

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Integrin β3 Inhibition Enhances the Antitumor Activity of ALK Inhibitor in ALK-Rearranged NSCLC

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Non–Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases

Cited by 116 publications

References 39 publications

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

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

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Integrin β3 Inhibition Enhances the Antitumor Activity of ALK Inhibitor in ALK-Rearranged NSCLC

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Product

Resources

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

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