Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Rong Wang, Tadaaki Yamada (), Kenji Kita, Hirokazu Taniguchi, Sachiko Arai, Koji Fukuda, Minoru Terashima, Akihiko Ishimura, Akihiro Nishiyama, Azusa Tanimoto, Shinji Takeuchi, Koshiro Ohtsubo, Kaname Yamashita, Tomoyoshi Yamano, Akihiro Yoshimura, Koichi Takayama, Kyoichi Kaira, Yoshihiko Taniguchi, Shinji Atagi, Hisanori Uehara, Rikinari Hanayama, Isao Matsumoto, Xujun Han, Kunio Matsumoto, Wei Wang (), Takeshi Suzuki and Seiji Yano ()
Additional contact information
Rong Wang: Kanazawa University
Tadaaki Yamada: Kanazawa University
Kenji Kita: Kanazawa University
Hirokazu Taniguchi: Kanazawa University
Sachiko Arai: Kanazawa University
Koji Fukuda: Kanazawa University
Minoru Terashima: Kanazawa University Kanazawa
Akihiko Ishimura: Kanazawa University Kanazawa
Akihiro Nishiyama: Kanazawa University
Azusa Tanimoto: Kanazawa University
Shinji Takeuchi: Kanazawa University
Koshiro Ohtsubo: Kanazawa University
Kaname Yamashita: Kanazawa University
Tomoyoshi Yamano: Kanazawa University
Akihiro Yoshimura: Kyoto Prefectural University of Medicine
Koichi Takayama: Kyoto Prefectural University of Medicine
Kyoichi Kaira: Saitama Medical University
Yoshihiko Taniguchi: National Hospital Organization Kinki-chuo Chest Medical Center
Shinji Atagi: National Hospital Organization Kinki-chuo Chest Medical Center
Hisanori Uehara: Tokushima University Hospital
Rikinari Hanayama: Kanazawa University
Isao Matsumoto: Kanazawa University
Xujun Han: Kanazawa University
Kunio Matsumoto: Kanazawa University
Wei Wang: Southern Medical University
Takeshi Suzuki: Kanazawa University Kanazawa
Seiji Yano: Kanazawa University

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.

Date: 2020
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DOI: 10.1038/s41467-020-18442-4

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