Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer
Open accessAbstract
Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.
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Inhibition of the FGFR signaling pathway reduces ERK and mTOR activation, whereas AXL inhibition attenuates the activation of PI3K pathway.
“Inhibition of the FGFR signaling pathway reduces ERK and mTOR activation, whereas AXL inhibition attenuates the activation of PI3K pathway [43, 136–139].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [43]
High feedback activation of the FGFR/AXL signaling pathway was found in mesenchymal cells.
“High feedback activation of the FGFR/AXL signaling pathway was found in mesenchymal cells.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [43]
In the context of an EMT, AXL upregulation appears as a novel mechanism of acquired EGFR-TKI resistance in EGFR-mutant NSCLCs.
“In the context of an EMT, AXL upregulation appears as a novel mechanism of acquired EGFR-TKI resistance in EGFR-mutant NSCLCs.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [40]
An EMT-associated transcriptional programme involving upregulation of vimentin may, in part, drive AXL overexpression in EGFR-mutant lung cancer cells with acquired EGFR-TKI resistance.
“Therefore, an EMT-associated transcriptional programme involving upregulation of vimentin may, in part, drive AXL overexpression in EGFR-mutant lung cancer cells with acquired EGFR-TKI resistance.40”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [40]
Pharmacological inhibition of AXL significantly decreased the proliferative and invasive abilities of cancer cells and increased their chemosensitivity through inhibition of AKT and MAPK pathways.
“Pharmacological inhibition of AXL significantly decreased the proliferative and invasive abilities of cancer cells and increased their chemosenstivity through inhibition of AKT and MAPK pathways.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [40]
Rare EGFR point mutations (<10% of patients) that result in resistance include Asp761Tyr, Thr854Ala, and Leu747Ser; the mechanism underlying resistance conferred by these mutations is still unclear.
“Rare EGFR point mutations (<10% of patients) that result in resistance include Asp761Tyr,39 Thr854Ala,40 and Leu747Ser. The mechanism (or mechanisms) underlying resistance conferred by these mutations is still unclear.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [40]
An integrated analysis in human EGFR-mutant NSCLC models and in a large clinical cohort of paired NSCLC specimens from EGFR-TKI-treated patients demonstrated an upregulation of AXL tyrosine kinase receptor or of its ligand, GAS6, in resistant samples.
“Recently, an integrated analysis in human EGFR-mutant NSCLC models and in a large clinical cohorts of paired NSCLC specimens from EGFR-TKI-treated patients demonstrated an upregulation of AXL tyrosine kinase receptor or of its ligand, GAS6, in resistant samples.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [40]
An AXL mutation was observed in one case with acquired T790M/C797S, suggesting association with EMT.
“We observed an AXL mutation in one case with acquired T790M/C797S (Pt. 12 Supple Table 2)[24], suggesting association with EMT.”
From Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in <i>EGFR</i> -Mutant NSCLC (2018) · cites this paper as [24]
AXL inhibition sensitizes drug-resistant mesenchymal tumor cells to anticancer agents, including antimitotic agents, EGFR inhibitors, and PI3K inhibitors.
“AXL inhibition has been reported to sensitize drug-resistant mesenchymal tumor cells to anticancer agents, including antimitotic agents, epidermal growth factor receptor (EGFR) inhibitors, and PI3K inhibitors”
From Hypoxic control of metastasis (2016) · cites this paper as [84]
In erlotinib-resistant EGFR mutant lung cancer cells and lapatinib-resistant HER2-amplified breast cancer cells, levels of the AXL RTK were markedly increased.
“Finally, in erlotinib-resistant EGFR mutant lung cancer cells and lapatinib-resistant HER2-amplified breast cancer cells, levels of the AXL RTK were markedly increased (Liu et al., 2009; Zhang et al., 2012).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Zhang et al., 2012
Targeting AXL re-sensitized some resistant cancers to the original TKI.
“Targeting AXL was able to re-sensitize some of these resistant cancers to the original TKI.”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Zhang et al., 2012
In resistance mediated by IGF-IR and AXL, inhibition of the bypass RTK in combination with EGFR is needed to overcome resistance.
“In similar examples of resistance mediated by IGF-IR and AXL, inhibition of the bypass RTK in combination with the EGFR is needed to overcome resistance (Cortot et al., 2013; Guix et al., 2008; Zhang et al., 2012).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Zhang et al., 2012
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- Authors
- Zhang, Z., Lee, J. C., Lin, L., Olivas, V., Au, V., LaFramboise, T., Abdel-Rahman, M., Wang, X., Levine, A. D., Rho, J. K., Choi, Y. J., Choi, C.-M., Kim, S.-W., Jang, S. J., Park, Y. S., Kim, W. S., Lee, D. H., Lee, J.-S., Miller, V. A., Arcila, M., Ladanyi, M., Moonsamy, P., Sawyers, C., Boggon, T. J., Ma, P. C., Costa, C., Taron, M., Rosell, R., Halmos, B., & Bivona, T. G.
- Affiliations
- Columbia University Irving Medical Center (US)
- Asan Medical Center (KR)
- University of California, San Francisco (US)
- University Hospitals Cleveland Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Yale University (US)
- Cleveland Clinic (US)
- Institut Català d'Oncologia (ES)
- Corresponding author
- Bivona, Trever G
- ORCID
- Zhang, Zhenfeng
- Lee, Jae Cheol
- Lin, Luping
- LaFramboise, Thomas
- Wang, Xiaoqi
- Levine, Alan D
- Rho, Jin Kyung
- Choi, Yun Jung
- Choi, Chang-Min
- Jang, Se Jin
- Park, Young Soo
- Kim, Woo Sung
- Lee, Dae Ho
- Lee, Jung-Shin
- Miller, Vincent A
- Arcila, Maria
- Ladanyi, Marc
- Moonsamy, Philicia
- Sawyers, Charles
- Boggon, Titus J
- Rosell, Rafael
- Bivona, Trever G
- Venue
- Nature Genetics
- Published
- 2012-07-01
- Volume
- 44
- Issue
- 8
- Pages
- 852-860
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3408577
- OpenAlex
- W1983774108
- Cited by
- 1,224
- References
- 29
- Citations by year
- 2026: 37 · 2025: 61 · 2024: 49 · 2023: 85 · 2022: 73 · 2021: 86 · 2020: 101 · 2019: 89 · 2018: 103 · 2017: 112 · 2016: 116 · 2015: 131 · 2014: 82 · 2013: 82 · 2012: 14
- FWCI
- 80.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T35HL007616)
- National Cancer Institute (R01CA169338, DP2CA174497, P01CA129243, K08CA154787, K08 1K08CA154787)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- AXL kinase, erlotinib resistance, EGFR-mutant lung cancer, non-small cell lung cancer, tyrosine kinase inhibitors, epithelial-mesenchymal transition, Gas6, acquired drug resistance, therapeutic target, MET kinase
- MeSH terms
- Erlotinib Hydrochloride, Axl Receptor Tyrosine Kinase, Growth Arrest-Specific Protein 6, Adult, Aged, Animals, Carcinoma, Non-Small-Cell Lung, Enzyme Activation, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Proto-Oncogene Proteins, Quinazolines, Signal Transduction, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-met, Receptor Protein-Tyrosine Kinases, Xenograft Model Antitumor Assays, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Protein Kinase Inhibitors, Epithelial-Mesenchymal Transition, ErbB Receptors
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