論文 - 詳細
| RRC ID | 65151 |
|---|---|
| 著者 | Suzawa K, Offin M, Lu D, Kurzatkowski C, Vojnic M, Smith RS, Sabari JK, Tai H, Mattar M, Khodos I, de Stanchina E, Rudin CM, Kris MG, Arcila ME, Lockwood WW, Drilon A, Ladanyi M, Somwar R. |
| タイトル | Activation of KRAS Mediates Resistance to Targeted Therapy in MET Exon 14-mutant Non-small Cell Lung Cancer. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:MET exon 14 splice site alterations that cause exon skipping at the mRNA level (METex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear. EXPERIMENTAL DESIGN:We examined clinical and genomic data from 113 patients with lung cancer with METex14. MET TKI resistance due to KRAS mutation was functionally evaluated using in vivo and in vitro models. RESULTS:Five of 113 patients (4.4%) with METex14 had concurrent KRAS G12 mutations, a rate of KRAS cooccurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the KRAS mutation was acquired post-crizotinib, while the remaining 4 METex14 patients harbored the KRAS mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with METex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that KRAS mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models. CONCLUSIONS:KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in METex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort. |
| 巻・号 | 25(4) |
| ページ | 1248-1260 |
| 公開日 | 2019-2-15 |
| DOI | 10.1158/1078-0432.CCR-18-1640 |
| PII | 1078-0432.CCR-18-1640 |
| PMID | 30352902 |
| PMC | PMC6377821 |
| MeSH | Aged Animals Carcinoma, Non-Small-Cell Lung / drug therapy* Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / pathology Crizotinib / administration & dosage Drug Resistance, Neoplasm / drug effects ErbB Receptors / antagonists & inhibitors ErbB Receptors / genetics Exons / drug effects Female Gene Expression Regulation, Neoplastic / drug effects Heterografts High-Throughput Nucleotide Sequencing Humans MAP Kinase Kinase Kinases / antagonists & inhibitors MAP Kinase Kinase Kinases / genetics Male Mice Middle Aged Molecular Targeted Therapy Mutation Protein Kinase Inhibitors / administration & dosage* Proto-Oncogene Proteins c-met / antagonists & inhibitors* Proto-Oncogene Proteins c-met / genetics Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors* Proto-Oncogene Proteins p21(ras) / genetics Receptor, ErbB-2 / antagonists & inhibitors Receptor, ErbB-2 / genetics |
| IF | 10.107 |
| リソース情報 | |
| ヒト・動物細胞 | PC-9(RCB4455) |