Abstract
The ROS1 tyrosine kinase is activated in lung cancer as a consequence of chromosomal rearrangement. Although high response rates and disease control have been observed in lung cancer patients bearing rearranged ROS1 tumors (ROS1+) treated with the kinase inhibitor crizotinib, many of these patients eventually relapse.To identify mechanisms of resistance to ROS1 inhibitors we generated resistant cells from HCC78 lung cancer cells bearing the SLC34A2-ROS1 rearrangement. We found that activation of the RAS pathway in the HCC78 cell model, due to either KRAS/NRAS mutations or to KRAS amplification, rendered the cells resistant to ROS1 inhibition. These cells were cross-resistant to different ROS1 inhibitors, but sensitive to inhibitors of the RAS signaling pathway. Interestingly, we identified focal KRAS amplification in a biopsy of a tumor from a patient that had become resistant to crizotinib treatment.Altogether our data suggest that the activation of members of the RAS family can confer resistance to ROS1 inhibitors. This has important clinical implications as: (i) RAS genetic alterations in ROS1+ primary tumors are likely negative predictors of efficacy for targeted drugs and (ii) this kind of resistance is unlikely to be overcome by the use of more specific or more potent ROS1 targeting drugs.
Keywords:
RAS; ROS1; drug resistance; lung cancer; targeted therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis
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Blotting, Western
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology*
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Cell Proliferation
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Crizotinib
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Drug Resistance, Neoplasm / genetics*
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Gene Rearrangement
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Humans
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Immunoenzyme Techniques
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In Situ Hybridization, Fluorescence
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Mutation / genetics
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Protein Kinase Inhibitors / pharmacology*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins p21(ras)
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Pyrazoles / pharmacology*
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Pyridines / pharmacology*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Sodium-Phosphate Cotransporter Proteins, Type IIb / genetics
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Sodium-Phosphate Cotransporter Proteins, Type IIb / metabolism
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Tumor Cells, Cultured
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ras Proteins / genetics*
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ras Proteins / metabolism
Substances
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KRAS protein, human
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyrazoles
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Pyridines
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RNA, Messenger
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SLC34A2 protein, human
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Sodium-Phosphate Cotransporter Proteins, Type IIb
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Crizotinib
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Protein-Tyrosine Kinases
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ROS1 protein, human
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Proto-Oncogene Proteins p21(ras)
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ras Proteins