AXL Mediates Cetuximab and Radiation Resistance Through Tyrosine 821 and the c-ABL Kinase Pathway in Head and Neck Cancer

McDaniel, Nellie K.; Iida, Mari; Nickel, Kwangok P.; Longhurst, Colin A.; Fischbach, Samantha R.; Rodems, Tamara S.; Kranjac, Carlene A.; Bo, Amber Y.; Luo, Qianyun; Gallagher, Meghan M.; Welke, Noah B.; Mitchell, Kaitlyn R.; Schulz, Alison E.; Eckers, Jaimee C.; Hu, Rong; Salgia, Ravi; Hong, Seungpyo; Bruce, Justine Y.; Kimple, Randall J.; Wheeler, Deric L.

doi:10.1158/1078-0432.ccr-19-3142

Cited by 30 publications

(29 citation statements)

References 50 publications

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“…Recently, McDaniel et al. investigated the AXL-mediated CTX-resistance mechanisms in HNSCC and report that the tyrosine 821 of AXL mediates resistance to CTX by activation of c-ABL (oncoprotein) ( 156 ).…”

Section: Mechanisms Of Resistance To Cetuximabmentioning

confidence: 99%

“…Combined with CTX, MET inhibitor PHA-665752 is also shown to restore CTX sensitivity in vitro and in vivo , especially by decreasing akt and ERK1/2 phosphorylation ( 146 , 147 ). Inhibition of the AXL receptor is explored by using imatinib (which targets c-Abl) in CTX-resistant HNSCC PDX ( 156 ). This led to complete tumor regression and a prolonged effect (no recurrence up to 3 months after cessation of treatment).…”

Section: Mechanisms Of Resistance To Cetuximabmentioning

confidence: 99%

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Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers

et al. 2021

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most incident cancer worldwide. More than half of HNSCC patients experience locoregional or distant relapse to treatment despite aggressive multimodal therapeutic approaches that include surgical resection, radiation therapy, and adjuvant chemotherapy. Before the arrival of immunotherapy, systemic chemotherapy was previously employed as the standard first-line protocol with an association of cisplatin or carboplatin plus 5-fluorouracil plus cetuximab (anti-EFGR antibody). Unfortunately, acquisition of therapy resistance is common in patients with HNSCC and often results in local and distant failure. Despite our better understanding of HNSCC biology, no other molecular-targeted agent has been approved for HNSCC. In this review, we outline the mechanisms of resistance to the therapeutic strategies currently used in HNSCC, discuss combination treatment strategies to overcome them, and summarize the therapeutic regimens that are presently being evaluated in early- and late-phase clinical trials.

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Section: Mechanisms Of Resistance To Cetuximabmentioning

confidence: 99%

Section: Mechanisms Of Resistance To Cetuximabmentioning

confidence: 99%

Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers

et al. 2021

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“…The technology offers precise and sensitive multiplexed quantification of the abundance of proteins and posttranslational modifications in hundreds of arrayed samples, providing the opportunity for high-throughput proteomic profiling of cells and tissues [13][14][15] . RPPA therefore provides a valuable tool for the targeted analysis of disease-relevant signaling mechanisms, including in cancer [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] .…”

Section: Background and Summarymentioning

confidence: 99%

Multicenter reverse-phase protein array data integration

Koning

Bernhardt

Macleod

et al. 2021

Preprint

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Among the technologies available for protein biomarker discovery and validation, reverse-phase protein array (RPPA) benefits from unequalled sample throughput. Panels of high-quality antibodies enable the quantification by RPPA of protein abundance and posttranslational modifications in biological specimens with high precision and sensitivity. Incorporation of RPPA technology into clinical and drug development pipelines requires robust assays that generate reproducible results across multiple laboratories. We implemented the first international multicenter pilot study to investigate RPPA workflow variability. We characterized the proteomic responses of a series of breast cancer cells to two cancer drugs. This analysis quantified 86,832 sample spots, representing 108 biological samples, arrayed at three independent RPPA platforms. This unique integrated set of data is publicly available as a resource to the proteomic and cancer research communities to catalyse further analysis and investigation. We anticipate that this dataset will form a reference for the comparison of RPPA workflows and reagents, which can be expanded in the future, and will aid the identification of platform-robust treatment-marker antigens in breast cancer cells.

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“…To verify the involvement of SCF/c-kit signaling pathways in mediating acquired pyrotinib resistance, we evaluated imatinib, a c-kit inhibitor, in acquired pyrotinib resistance in HER2-positive models both in vitro and in vivo [17,18]. As shown in Fig.…”

Section: Imatinib Enhances the Sensitivity Of Nci-n87-ar Cells To Pyrmentioning

confidence: 99%

Apatinib exhibits synergistic effect with pyrotinib and reverses acquired pyrotinib resistance in HER2-positive gastric cancer via stem cell factor/c-kit signaling and its downstream pathways

Huang

Jin

et al. 2020

Gastric Cancer

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Background Recently, progress has been made in the development of targeted therapies for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). However, drug resistance has severely limited the efficacy of anti-HER2 therapies. Pyrotinib is a novel pan-HER inhibitor. Although it is effective in HER2-positive GC treatment, its efficacy in combination with apatinib and associated resistance mechanisms in HER2-positive GC remains unclear. Methods In this study, the combination effects of pyrotinib and apatinib were examined in two pyrotinib-sensitive GC cells and xenografts. The RNA sequencing was used to determine the underlying mechanisms of acquired pyrotinib resistance. The role of imatinib and apatinib in reversing pyrotinib resistance was tested in pyrotinib-resistant cells and xenografts. Results Here, we reported that a combination of pyrotinib and apatinib exhibits synergistic effect in HER2-positive NCI-N87 xenografts, and showed enhanced antitumor efficacy in HER2-positive GC, both in vitro and in vivo. Moreover, up-regulation of the stem cell factor (SCF) levels, and the PI3K/AKT and MAPK pathways was associated with acquired pyrotinib resistance in HER2-positive GC. Mechanistically, we demonstrated that the activation of the SCF/c-kit signaling and its downstream PI3K/AKT and MAPK pathways mediated pyrotinib resistance by promoting cell survival and proliferation. Imatinib and apatinib augmented the sensitivity of pyrotinib-resistant cells and xenografts to pyrotinib, by blocking SCF/c-kit signaling. Conclusion These results highlight the effectiveness of pyrotinib combined with apatinib in HER2-positive GC and acquired pyrotinib resistance, thus providing a theoretical basis for new treatment methods.

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AXL Mediates Cetuximab and Radiation Resistance Through Tyrosine 821 and the c-ABL Kinase Pathway in Head and Neck Cancer

Cited by 30 publications

References 50 publications

Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers

Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers

Multicenter reverse-phase protein array data integration

Apatinib exhibits synergistic effect with pyrotinib and reverses acquired pyrotinib resistance in HER2-positive gastric cancer via stem cell factor/c-kit signaling and its downstream pathways

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