AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells
Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved..
Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:587 |
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| Enthalten in: |
Cancer letters - 587(2024) vom: 10. März, Seite 216692 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Morimoto, Kenji [VerfasserIn] |
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| Links: |
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| Themen: |
AXL |
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| Anmerkungen: |
Date Completed 26.03.2024 Date Revised 26.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.canlet.2024.216692 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368317978 |
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| 100 | 1 | |a Morimoto, Kenji |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells |
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| 500 | |a Date Revised 26.03.2024 | ||
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AXL | |
| 650 | 4 | |a Adaptive resistance | |
| 650 | 4 | |a KRAS G12C | |
| 650 | 7 | |a Proto-Oncogene Proteins p21(ras) |2 NLM | |
| 650 | 7 | |a EC 3.6.5.2 |2 NLM | |
| 650 | 7 | |a KRAS protein, human |2 NLM | |
| 700 | 1 | |a Yamada, Tadaaki |e verfasserin |4 aut | |
| 700 | 1 | |a Hirai, Soichi |e verfasserin |4 aut | |
| 700 | 1 | |a Katayama, Yuki |e verfasserin |4 aut | |
| 700 | 1 | |a Fukui, Sarina |e verfasserin |4 aut | |
| 700 | 1 | |a Sawada, Ryo |e verfasserin |4 aut | |
| 700 | 1 | |a Tachibana, Yusuke |e verfasserin |4 aut | |
| 700 | 1 | |a Matsui, Yohei |e verfasserin |4 aut | |
| 700 | 1 | |a Nakamura, Ryota |e verfasserin |4 aut | |
| 700 | 1 | |a Ishida, Masaki |e verfasserin |4 aut | |
| 700 | 1 | |a Kawachi, Hayato |e verfasserin |4 aut | |
| 700 | 1 | |a Kunimasa, Kei |e verfasserin |4 aut | |
| 700 | 1 | |a Sasaki, Takaaki |e verfasserin |4 aut | |
| 700 | 1 | |a Nishida, Makoto |e verfasserin |4 aut | |
| 700 | 1 | |a Furuya, Naoki |e verfasserin |4 aut | |
| 700 | 1 | |a Watanabe, Satoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Shiotsu, Shinsuke |e verfasserin |4 aut | |
| 700 | 1 | |a Nishioka, Naoya |e verfasserin |4 aut | |
| 700 | 1 | |a Horinaka, Mano |e verfasserin |4 aut | |
| 700 | 1 | |a Sakai, Toshiyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Uehara, Hisanori |e verfasserin |4 aut | |
| 700 | 1 | |a Yano, Seiji |e verfasserin |4 aut | |
| 700 | 1 | |a Son, Bo-Kyung |e verfasserin |4 aut | |
| 700 | 1 | |a Tokuda, Shinsaku |e verfasserin |4 aut | |
| 700 | 1 | |a Takayama, Koichi |e verfasserin |4 aut | |
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