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Foretinib can overcome common on-target resistance mutations after capmatinib/tepotinib treatment in NSCLCs with MET
Toshio Fujino1, Kenichi Suda1, Takamasa Koga1
1Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
Background:
Capmatinib 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.
Methods:
The 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.
Results:
All 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.
Conclusions:
The 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.
Insights
Foretinib shows promise as a second-line treatment for non-small-cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations (METex14) who develop resistance to capmatinib or tepotinib due to specific MET mutations. This study identifies foretinib as active against D1228X mutations, offering a potential new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Capmatinib and tepotinib are first-line treatments for non-small-cell lung cancer (NSCLC) with MET exon 14 skipping mutations (METex14).
- Acquired resistance to these treatments often arises from secondary MET mutations, specifically D1228X or Y1230X.
- Identifying agents effective against these resistance mutations is crucial for sequential therapy.
Purpose of the Study:
- To screen for drugs active against MET D1228X and Y1230X secondary mutations.
- To identify an ideal sequential treatment for NSCLC patients with METex14 after capmatinib/tepotinib failure.
Main Methods:
- Screened 300 drugs, including 33 MET-TKIs, for inhibitory effects on Ba/F3 cells with METex14 and D1228A/Y mutations.
- Performed growth inhibition assays with selected MET-TKIs on cells harboring various D1228X or Y1230X mutations.
- Utilized in vitro and in vivo Hs746t cell models and molecular dynamics (MD) simulations to confirm findings and analyze binding.
Main Results:
- All tested type II MET-TKIs inhibited Y1230X mutations.
- Foretinib demonstrated potent activity against D1228X mutations in both cell models and in vivo, while CEP-40783 and altiratinib showed some activity.
- MD analysis indicated foretinib's long tail is key for D1228X binding; tertiary mutations (G1163X, L1195F/I, F1200I/L) emerged as resistance mechanisms to foretinib.
Conclusions:
- Foretinib is a potential second-line treatment for NSCLC patients with METex14 whose tumors develop D1228X or Y1230X secondary mutations after capmatinib/tepotinib therapy.
- Understanding resistance mechanisms to foretinib is essential for optimizing sequential treatment strategies.
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