Gastrointestinal malignancies harbor actionable MET exon 14 deletions

Abstract

Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies.

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

“…Moreover, as described in lung cancer (24), MET exon 14 skipping mutations occur mutually exclusively with other validated drivers, thus supporting its oncogenic implication and defining a distinct molecular subgroup of gastrointestinal malignancies (29). In the preclinical analysis included in the study, the growth of two patientderived tumor cell lines harboring MET exon 14 deletion (one from gastric and one from colon cancer) were strongly inhibited by both Met TKI and an anti-Met monoclonal antibody (29). Furthermore, two independent preclinical studies reported the presence of MET exon 14 deletion in gastric cancer cell lines (58,59).…”

“…Interestingly, all the MET exon 14 positive cases showed also Met protein overexpression, without the coexistence of a MET amplification (reported in only one case). Moreover, as described in lung cancer (24), MET exon 14 skipping mutations occur mutually exclusively with other validated drivers, thus supporting its oncogenic implication and defining a distinct molecular subgroup of gastrointestinal malignancies (29). In the preclinical analysis included in the study, the growth of two patientderived tumor cell lines harboring MET exon 14 deletion (one from gastric and one from colon cancer) were strongly inhibited by both Met TKI and an anti-Met monoclonal antibody (29).…”

“…A series of 230 solid tumor specimens, including 42 gastric and 43 colon cancer samples, was examined using multiplexed fusion transcript detection assay, confirmed with reverse transcription PCR (RT-PCR) and then correlated with Met protein overexpression (29). The data generated by quantitative RT-PCR confirmed the presence of the MET exon 14 skipping mutations in three cases (7.1%) in gastric cancer and five cases (9.3%) in colon cancer.…”

Structurally and mechanically tunable molybdenum oxide films and patterned submicrometer structures by electrodeposition

“…Transition metal oxides in thin-film form have received much attention owing to their promising applications in electrochromics, energy storage, sensing, and non-volatile resistive random access memory devices, among others [1][2][3]. Molybdenum oxide is a suitable candidate in many of these applications due to its unusual chemistry produced by multiple Mo valence states (IV, V and VI) and a rich variety of crystallographic structures [3,4].…”

“…For example, amorphous molybdenum oxide is suitable as an electrochemical sensor for iodate ions [14], whereas MoO 3 nanocrystalline films and nanorods can serve as gas sensors toward H 2 [15] and NO 2 [16], respectively. In addition, nanostructured α-MoO 3 has been applied as supercapacitor electrodes in acid aqueous electrolytes [17].…”