Inhibition of Axl improves the targeted therapy against ALK-mutated neuroblastoma

Xu, Fei; Li, Hongling; Sun, Yong

doi:10.1016/j.bbrc.2014.10.126

Cited by 14 publications

(18 citation statements)

References 19 publications

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“…For example, therapeutic resistance to ALK inhibitors is well documented for ALK-positive NSCLC and is known to arise through both ALK-dependent and -independent mechanisms 20 . ALK inhibitors are undergoing clinical assessment for ALKpositive pediatric malignancies including NB 50,51 , and growing evidence from preclinical studies indicates that both de novo and acquired resistance will be of concern 13,[16][17][18][19] . In this study, we proactively investigated mechanisms of resistance to ALK inhibitors using CRISPRa screens in NB cell lines harboring recurrent point mutations in the ALK tyrosine kinase domain, including those previously shown to confer endogenous resistance to the ALK inhibitor crizotinib.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous recent studies have demonstrated the efficacy of ALK inhibitors against ALK-positive NB cell lines and patient-derived xenografts [13][14][15] . Several of these studies have documented the de novo resistance of the ALK F1174L mutation to crizotinib and ceritinib, and have devised combinatorial treatment strategies to enhance efficacy 13,[16][17][18][19] .…”

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confidence: 99%

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The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

et al. 2019

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Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

et al. 2019

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“…Treatment of SH-SY5Y xenograft mice with AZD3463 for 21 days resulted in complete tumor regression while a significant regression was observed in NGP xenograft mice. One possible explanation is that NB cells with ALK aberration (mutation or amplification) are ALK addictive 20 32 . Moreover, NGP is well known to be a more malignant NB cell characterized with MYCN amplification but without ALK amplification.…”

Section: Discussionmentioning

confidence: 99%

Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis

Wang

Guan

et al. 2016

Sci Rep

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ALK receptor tyrosine kinase has been shown to be a therapeutic target in neuroblastoma. Germline ALK activating mutations are responsible for the majority of hereditary neuroblastoma and somatic ALK activating mutations are also frequently observed in sporadic cases of advanced NB. Crizotinib, a first-line therapy in the treatment of advanced non-small cell lung cancer (NSCLC) harboring ALK rearrangements, demonstrates striking efficacy against ALK-rearranged NB. However, crizotinib fails to effectively inhibit the activity of ALK when activating mutations are present within its kinase domain, as with the F1174L mutation. Here we show that a new ALK inhibitor AZD3463 effectively suppressed the proliferation of NB cell lines with wild type ALK (WT) as well as ALK activating mutations (F1174L and D1091N) by blocking the ALK-mediated PI3K/AKT/mTOR pathway and ultimately induced apoptosis and autophagy. In addition, AZD3463 enhanced the cytotoxic effects of doxorubicin on NB cells. AZD3463 also exhibited significant therapeutic efficacy on the growth of the NB tumors with WT and F1174L activating mutation ALK in orthotopic xenograft mouse models. These results indicate that AZD3463 is a promising therapeutic agent in the treatment of NB.

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“…Additionally, AXL has been implicated in resistance to a variety of other targeted therapies in other cancer types, including vemurafenib, sunitinib, alpelisib, crizotinib, and imatinib [86][87][88][89][90]. Resistance to such diverse therapies is likely linked to AXL's role in mediating EMT, which has long been associated with chemoresistance.…”

Section: Targeted Erapiesmentioning

confidence: 99%

AXL as a Target in Breast Cancer Therapy

Colavito

2020

Journal of Oncology

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AXL is a receptor tyrosine kinase (RTK) that has been implicated in diverse tumor-promoting processes such as proliferation, migration, invasion, survival, and apoptosis. AXL therefore plays a role in cancer progression, and AXL has been implicated in a wide variety of malignancies from solid tumors to hematopoietic cancers where it is often associated with poor prognosis. In cancer, AXL has been shown to promote epithelial to mesenchymal transition (EMT), metastasis formation, drug resistance, and a role for AXL in modulation of the tumor microenvironment and immune response has been identified. In light of these activities multiple AXL inhibitors have been developed, and several of these have entered clinical trials in the U.S. In breast cancer, high levels of AXL expression have been observed. The role of AXL in cancer with a focus on therapeutic implications for breast cancer is discussed.

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Inhibition of Axl improves the targeted therapy against ALK-mutated neuroblastoma

Cited by 14 publications

References 19 publications

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis

AXL as a Target in Breast Cancer Therapy

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