Dataset Information

MET D1228N and D1246N are the Same Resistance Mutation in MET Exon 14 Skipping.

ABSTRACT: Comprehensive genetic profiling using next-generation sequencing technologies has become an integral part of precision oncology. Variant annotation requires translating the DNA findings into protein level predictions. In this article we highlight inconsistencies in variant annotation for the MET D1228N exon 19 resistance mutations. MET D1228N and D1246N represent the same resistance mutation in MET exon 14 skipping alterations annotated on different transcripts. Additional examples of relevant variants annotated on different transcripts emphasize the importance of avoiding erroneous interpretation when realizing precision oncology.

SUBMITTER: Tsai JM

PROVIDER: S-EPMC8649016 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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MET D1228N and D1246N are the Same Resistance Mutation in MET Exon 14 Skipping.

Tsai Jonathan M JM Hata Aaron N AN Lennerz Jochen K JK

The oncologist 20210817 12

Comprehensive genetic profiling using next-generation sequencing technologies has become an integral part of precision oncology. Variant annotation requires translating the DNA findings into protein level predictions. In this article we highlight inconsistencies in variant annotation for the MET D1228N exon 19 resistance mutations. MET D1228N and D1246N represent the same resistance mutation in MET exon 14 skipping alterations annotated on different transcripts. Additional examples of relevant v ...[more]

PMID: 34347347

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Project description:BackgroundCapmatinib and tepotinib are guideline-recommended front-line treatments for non-small-cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations (METex14). However, the emergence of acquired resistance to capmatinib/tepotinib is almost inevitable partially due to D1228X or Y1230X secondary mutations of the MET. In this study, we explored agents that are active against both D1228X and Y1230X MET to propose an ideal sequential treatment after capmatinib/tepotinib treatment failure in NSCLC patients with METex14.MethodsThe inhibitory effects of 300 drugs, including 33 MET-TKIs, were screened in Ba/F3 cells carrying METex14 plus MET D1228A/Y secondary mutations. The screen revealed four-candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). Therefore, we performed further growth inhibitory assays using these four MET-TKIs plus cabozantinib and merestinib in Ba/F3 cells carrying MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations. We also performed analyses using Hs746t cell models carrying METex14 (with mutant allele amplification) with/without D1228X or Y1230X in vitro and in vivo to confirm the findings. Furthermore, molecular dynamics (MD) simulations were carried out to examine differences in binding between type II MET-TKIs.ResultsAll 6 type II MET-TKIs were active against Y1230X secondary mutations. However, among these 6 agents, only foretinib showed potent activity against D1228X secondary mutations of the MET in the Ba/F3 cell and Hs746t in vitro model and Hs746t in vivo model, and CEP-40783 and altiratinib demonstrated some activity. MD analysis suggested that the long tail of foretinib plays an important role in binding D1228X MET through interaction with a residue at the solvent front (G1163). Tertiary G1163X mutations, together with L1195F/I and F1200I/L, occurred as acquired resistance mechanisms to the second-line treatment foretinib in Ba/F3 cell models.ConclusionsThe type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230.

Dataset Information

MET D1228N and D1246N are the Same Resistance Mutation in MET Exon 14 Skipping.

Publications

MET D1228N and D1246N are the Same Resistance Mutation in MET Exon 14 Skipping.

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