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Transient IGF-1R Inhibition Combined with Osimertinib Eradicates AXL-Low

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Transient IGF-1R Inhibition Combined with Osimertinib Eradicates AXL-Low ARTICLE https://doi.org/10.1038/s41467-020-18442-4 OPEN Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer ✉ Rong Wang 1,2, Tadaaki Yamada 1,3,14 , Kenji Kita 1, Hirokazu Taniguchi 1,4, Sachiko Arai1, Koji Fukuda1,5, Minoru Terashima 6, Akihiko Ishimura 6, Akihiro Nishiyama1, Azusa Tanimoto 1, Shinji Takeuchi 1,5, Koshiro Ohtsubo1, Kaname Yamashita1, Tomoyoshi Yamano 7, Akihiro Yoshimura 3, Koichi Takayama3, Kyoichi Kaira 8, Yoshihiko Taniguchi 9, Shinji Atagi 9, Hisanori Uehara10, ✉ Rikinari Hanayama 5,7, Isao Matsumoto 11, Xujun Han 1,5,12, Kunio Matsumoto 5,12,13, Wei Wang 2,14 , 1234567890():,; ✉ Takeshi Suzuki6,13 & Seiji Yano 1,5,14 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. 1 Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. 2 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China. 3 Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. 4 Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 5 Nano Life Science Institute, Kanazawa University, Kanazawa, Japan. 6 Division of Functional Genomics, Cancer Research Institute, Kanazawa University Kanazawa, Kanazawa, Japan. 7 Department of Immunology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan. 8 Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Hidaka, Japan. 9 Department of Thoracic Oncology, National Hospital Organization Kinki-chuo Chest Medical Center, Sakai, Japan. 10 Division of Pathology, Tokushima University Hospital, Tokushima, Japan. 11 Department of Thoracic, Cardiovascular and General Surgery, Kanazawa University, Kanazawa, Japan. 12 Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. 13 Tumor Microenvironment Research Unit, Institute for Frontier Science Initiative, Kanazawa ✉ University, Kanazawa, Japan. 14These authors jointly supervised this work: Tadaaki Yamada, Wei Wang, Seiji Yano. email: [email protected]; [email protected]; [email protected] NATURE COMMUNICATIONS | (2020) 11:4607 | https://doi.org/10.1038/s41467-020-18442-4 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-18442-4 ung cancer is the leading cause of cancer-related deaths and HCC4011) and AXL-low- expressing (HCC4006, HCC827, Lworldwide, with non-small cell lung cancer (NSCLC) com- and H3255) EGFR-mutated NSCLC cell lines in vitro (Fig. 1 a, b). prising 85% of lung cancers. Immune checkpoint inhibitors, While osimertinib inhibited the viability of all EGFR-mutated including the anti-programmed death 1 (PD-1) antibody and the NSCLC cell lines tested in a dose-dependent manner, the IC50 anti-programmed death-ligand 1 (PD-L1) antibody, have been (half-maximum inhibitory concentration) values were lower in approved for the treatment of advanced-stage NSCLC and have AXL-low-expressing tumor cell lines compared to the AXL-high- been shown to cure a population of NSCLC patients even at an expressing tumor cell lines. These results, in the line of our advanced stage1,2. The therapeutic potential of ICIs encourages previous study, indicated that AXL-low-expressing EGFR-muta- the development of novel drug therapies which would dramati- ted NSCLC cells were more sensitive to osimertinib than AXL- cally improve the prognosis of advanced NSCLC. high-expressing EGFR-mutated NSCLC cells. However, regard- Osimertinib is a third-generation epidermal growth factor less of AXL expression, a small population of tumor cells survived receptor-tyrosine kinase inhibitor (EGFR-TKI), which selectively even after 72 h of exposure to 1 μmol/L osimertinib, suggesting inhibits mutated EGFR (e.g., EGFR with exon 19 deletion, L858R, osimertinib tolerance in these populations. and T790M) and spares wild type EGFR3. Osimertinib is effective Next, we retrospectively assessed the correlations between AXL in T790M-positive EGFR-mutated NSCLC patients refractory to expression and the clinical efficacy of osimertinib administered as classical type EGFR-TKIs, including gefitinib and erlotinib4. the first-line treatment in 29 patients with EGFR-mutated Furthermore, osimertinib is more efficient than gefitinib and NSCLC. Expression of AXL in the cell cytoplasm of pre-EGFR- erlotinib when given as the first-line treatment in EGFR-mutated TKI-treated tumor samples was evaluated using immunohisto- NSCLC5. However, almost all the patients will experience disease chemistry (IHC) staining and scored as very high (3+), high recurrence due to acquired resistance to osimertinib. Regarding (2+), low (1+), and no (0) expression of AXL (Supplementary acquired resistance to osimertinib, several mechanisms including Figure 1). Of the 29 EGFR-mutated NSCLC tumor specimens, resistance mutations in EGFR (C797S/C796D), MET amplifica- high (2+ to 3+) and low (no to 1+) AXL expression was tion, and the emergence of other driver oncogenes (KRAS observed in 6 (21%), and 23 (79%) specimens, respectively. The mutations, BRAF mutations, RET fusion, etc.) have been reported response rate to osimertinib in patients with AXL-low expression in EGFR-mutated lung cancer patients with or without EGFR- (16/23; 70%) was higher than that observed in AXL-high T790M mutation6–9. Considering the fact that the EGFR-T790M expression (3/6; 50%), especially, in patients with AXL scores of mutation occurs in a large population (60–70%) of EGFR- 3+, the responder to osimertinib treatment was none (0/2; 0%) mutated lung cancer patients who acquired resistance to first- (Fig. 1c). In addition, osimertinib trended to cause tumor generation EGFR-TKIs gefitinib and erlotinib10, these observa- shrinkage more remarkably in patients with AXL-low expression tions suggest that mechanisms of osimertinib resistance are much compared to AXL-high expression (p = 0.094) (Fig. 1d). Notably, more diverse, and thus acquired osimertinib resistance may be no complete response was achieved with osimertinib treatment in harder to be controlled. Recent studies have uncovered that a these 29 patients regardless of the AXL expression in tumors, small population of cells adapts to the initial treatment with indicating that small tumors remained as residual lesions with EGFR-TKIs as persisters, presenting the basis for acquired osimertinib treatment even in responders. These results suggested resistant lesions11. By elucidating the adaptation mechanism that in accordance with results in cell line experiments, though following the initial treatment with EGFR-TKIs, we could develop AXL-low-expressing EGFR-mutated NSCLCs are highly sensitive novel initiation therapies to eradicate tumor cells, and thereby to osimertinib, drug tolerance following the acquisition of further improve the outcome of advanced EGFR-mutated NSCLC resistance always occurs. by preventing the development of acquired resistance. To clarify the mechanisms of osimertinib tolerance, we Previously, we reported that in AXL-high-expressing EGFR- performed receptor-tyrosine kinase (RTK) array analysis compar- mutated NSCLC, a small population of tumor cells emerged ing AXL-low-expressing (HCC4006 and H3255) and AXL-high- tolerant to osimertinib as persisters by restoring the survival expressing (PC-9) EGFR-mutated NSCLC cell lines treated with signal from AXL associated with EGFR and HER3, and the or without osimertinib for 72 h. Among 49 RTKs, IGF-1R combined treatment with osimertinib and an AXL inhibitor phosphorylation was increased after osimertinib exposure in prevented the development of acquired resistance to osimerti- AXL-low-expressing tumor cell lines, but not in AXL-high- nib12. On the other hand, even in AXL-low-expressing EGFR- expressing tumor cell lines (Fig. 1e). Western blot analysis mutated NSCLC, a small population of tumor cells persist to demonstrated that while the evaluated EGFR-mutated NSCLC osimertinib and develop acquired resistant tumors. However, the cell lines expressed various levels of IGF-1R protein, AXL-low- underlying mechanisms remain unknown. expressing tumor cells reported higher levels of phosphorylated In the present study, we investigated the mechanism of toler- IGF-1R (pIGF-1R) compared to AXL-high tumor cell lines ance
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