Activation of the AXL Kinase Causes Resistance to EGFR-Targeted Therapy in Lung Cancer

By Zhenfeng Zhang, Jae Cheol Lee, Luping Lin, V. Olivas, Valerie Au, T. LaFramboise, M. Abdel-Rahman, Xiaoqi Wang, A. Levine, J. Rho and 20 more. Nature Genetics, 2012

1,168 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/d07ad26949ecd880527f79528c814b701c030bc0

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In Oncology

1. William Pao
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In Pulmonary and Respiratory Medicine

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Citations in the corpus

• Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer (2018, neutral): “Activation of other alternative pathways, including HER2 amplification [34], PIK3CA mutation [35], BRAF mutation, and increased expression of the receptor tyrosine kinase AXL, have been reported to promote acquired resistance to EGFR TKIs [36].”
• Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq (2016, neutral): “A second transcriptional program, negatively correlated with the MITF program and with PC4 and PC5 (Pearson correlation P<10−24), included AXL and NGFR (p75NTR), a marker of resistance to various targeted therapies (27, 28) and a putative melanoma cancer stem cell marker (29), respectively (Table S8”
• Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. (2015, background): “Other resistance mechanisms include mutations in PIK3CA (75), HER2 (79,82), BRAF (83), STAT3 (84), AXL kinase (85), CRKL amplification (86) and in 5%,the unexpected transformation into small cell lung cancer (75,76).”