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Mutant-Selective Irreversible EGFR Inhibitor, Naquotinib, Inhibits Tumor Growth in NSCLC Models with EGFR-Activating Mutations

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Mutant-Selective Irreversible EGFR Inhibitor, Naquotinib, Inhibits Tumor Growth in NSCLC Models with EGFR-Activating Mutations Published OnlineFirst May 15, 2019; DOI: 10.1158/1535-7163.MCT-18-0976 Small Molecule Therapeutics Molecular Cancer Therapeutics Mutant-Selective Irreversible EGFR Inhibitor, Naquotinib, Inhibits Tumor Growth in NSCLC Models with EGFR-Activating Mutations, T790M Mutation, and AXL Overexpression Hiroaki Tanaka, Hideki Sakagami, Naoki Kaneko, Satoshi Konagai, Hiroko Yamamoto, Takahiro Matsuya, Masatoshi Yuri,Yosuke Yamanaka, Masamichi Mori, Masahiro Takeuchi, Hiroyuki Koshio, Masaaki Hirano, and Sadao Kuromitsu Abstract First- and second-generation EGFR tyrosine kinase inhibi- patient-derived xenograft model, naquotinib induced tumor tors (TKI) are effective clinical therapies for patients with non– regression of NSCLC with EGFR-activating mutations with or small cell lung cancer (NSCLC) harboring EGFR-activating without T790M resistance mutation, whereas it did not sig- mutations. However, almost all patients develop resistance to nificantly inhibit WT EGFR signaling in skin. Furthermore, these drugs. The EGFR T790M mutation of EGFR is the most naquotinib suppressed tumor recurrence during the treatment predominant mechanism for resistance. In addition, activa- period of 90 days. In addition, unlike erlotinib and osimerti- tion of AXL signaling is one of the suggested alternative nib, naquotinib inhibited the phosphorylation of AXL and bypassing pathways for resistance to EGFR-TKIs. Here, we showed antitumor activity against PC-9 cells overexpressing report that naquotinib, a pyrazine carboxamide–based AXL in vitro and in vivo. Our findings suggest that naquotinib EGFR-TKI, inhibited EGFR with activating mutations, as well has therapeutic potential in patients with NSCLC with EGFR- as T790M resistance mutation while sparing wild-type (WT) activating mutations, T790M resistance mutation, and AXL EGFR. In in vivo murine xenograft models using cell lines and a overexpression. Introduction NSCLC. However, almost all patients eventually develop resis- tance to these drugs after a median of 10–13 months (10–13). EGFR mutations are detected in approximately 10% of non– The EGFR T790M mutation is the most predominant mecha- small cell lung cancer (NSCLC) in Caucasian patients and nism for acquired resistance, detected in approximately 50%– approximately 40% of NSCLC in East Asian patients (1–3). 60% of patients with clinical resistance to these EGFR- EGFR mutations lead to constitutive activation of EGFR sig- TKIs (14–17). naling, including the MAPK/ERK and PI3K/AKT pathways (4, 5) Several third-generation irreversible EGFR-TKIs, including and oncogenic transformation, such as increased malignant cell WZ4002, osimertinib, rociletinib, and olmutinib, have been survival, proliferation, invasion, metastatic spread, and tumor developed to target activating EGFR mutations, as well as angiogenesis in NSCLC (6, 7). The most common EGFR muta- T790M mutation while sparing wild-type (WT) EGFR because tions are deletion in exon 19 (del ex19) and leucine-to-arginine second-generation EGFR-TKIs cause dose-limiting epithelial substitution at amino acid position 858 (L858R) in exon 21 toxicities due to their activity against WT EGFR and the normal mutations, which together account for approximately 90% of physiologic role of this kinase in skin and gastrointestinal activating EGFR mutations in NSCLC (8, 9). tissues (18–23). Although osimertinib has been approved for The first-generation reversible EGFR tyrosine kinase inhibi- second-line treatment in patients with NSCLC with EGFR tors (TKI), gefitinib and erlotinib, and second-generation cova- T790M mutation, this therapeutic option is limited. lent EGFR-TKIs, afatinib and dacomitinib, dramatically Aside from the EGFR T790M resistance mutation, activation improve progression-free survival in patients with advanced of alternative bypassing pathways, such as the MET, HER2, or AXL signaling pathways, has also been indicated as a resistance mechanism to EGFR-TKIs (15–17, 24–29). AXL overexpression Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan. and AXL-mediated resistance have been detected in many human cancers, including breast cancer, pancreatic cancer, Note: Supplementary data for this article are available at Molecular Cancer – Therapeutics Online (http://mct.aacrjournals.org/). prostate cancer, and NSCLC (28 33). Increased AXL expression in tumors often results from pharmacologic selective pressure Corresponding Author: Hiroaki Tanaka, Drug Discovery Research, Astellas to multiple chemotherapies and targeted therapies (34). Inhi- Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. Phone: 81- 29-863-7001; Fax: 81-29-856-2558; E-mail: [email protected] bition of activated EGFR may trigger the tyrosine kinase switch to transactivation of AXL and its downstream pathways to Mol Cancer Ther 2019;18:1366–73 maintain tumor growth, given that they share the same down- doi: 10.1158/1535-7163.MCT-18-0976 stream pathways such as the MAPK/ERK and PI3K/AKT path- Ó2019 American Association for Cancer Research. ways (29, 35, 36). AXL may mediate acquired resistance to TKIs 1366 Mol Cancer Ther; 18(8) August 2019 Downloaded from mct.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst May 15, 2019; DOI: 10.1158/1535-7163.MCT-18-0976 Activity of Naquotinib in Non–Small Cell Lung Cancer Models in an epithelial-to-mesenchymal transition setting in EGFR- Pharmacokinetics studies mutant NSCLC (29, 32, 33). These findings suggest that AXL is a Plasma and tumor concentrations of naquotinib were deter- potential therapeutic target in patients with NSCLC with mined by LC-MS/MS (Shimadzu 20AD LC System 2, Shimadzu acquired resistance to EGFR-TKIs. Corporation and Triple Quad 5500, AB Sciex LLC). Naquotinib Here, we describe the preclinical in vitro and in vivo character- and deuterated naquotinib, used as an internal standard (IS), were istics of naquotinib, which has a selective inhibitory effect on added to 25 mL of mouse plasma and tumor homogenate contain- EGFR-activating mutations and T790M resistance mutation over ing 0.025% 2,2-dichlorovinyl dimethyl phosphate (Wako Pure WT. In addition, we show the inhibitory effect of naquotinib on Chemical Industries, Ltd.) with 300 mL of 0.5 mol/L NaHCO3 the AXL signaling pathway, an alternative bypassing pathway in solution (Kokusan Chemical Co., Ltd.) and 3 mL of tert-butyl the development of resistance to EGFR-TKIs. methyl ether (Kanto Chemical Co., Inc.), and the mixture was shaken and centrifuged. The organic layer was collected and evaporated to dryness under a stream of nitrogen gas at about Materials and Methods 40C. The residue was dissolved in 400 mL of 50 mmol/L Reagents NH4HCO3 buffer (Kanto Chemical Co., Inc.)/acetonitrile (Koku- m Naquotinib and erlotinib were prepared at Astellas Pharma Inc. san Chemical Co., Ltd.; 45:55, v/v), and 3 L of the resulting as described in PCT Patent Application WO 2016/121777 and solution was injected into the LC-MS/MS. The analytic column  WO2001/34574, respectively. Afatinib and osimertinib were was a CAPCELL PAK C18 MGII (3.0 mm inner diameter 75 mm, m synthesized according to the PCT Patent Application WO particle size 3 m, Shiseido Co., Ltd.) and the mobile phase 2002/50043 and WO 2013/014448, respectively. comprised of 50 mmol/L NH4HCO3 buffer (45%) and acetoni- trile (55%). The parent and product ions, m/z 563 and m/z 323 for naquotinib, and m/z 571 and m/z 323 for the IS, respectively, Cell lines and cell culture were monitored using positive multiple reaction monitoring. The NCI-H1975, HCC827, NCI-H292, and NCI-H1666 were IS method with peak area ratio was used to determine levels of obtained from ATCC in 2012, 2012, 2008, and 2008, respec- naquotinib. tively. PC-9 was obtained from Immuno-Biological Laborato- ries in 2011. II-18, A431, and Ba/F3 were obtained from RIKEN In vivo xenograft studies BRC Cell Bank in 2013, 2013, and 2008, respectively. Cells All animal experimental procedures were approved by the were cultured in RPMI1640 medium supplemented with 10% Institutional Animal Care and Use Committee of Astellas heat-inactivated FBS at 37Cin5%CO atmosphere. The cell 2 Pharma Inc. Furthermore, Astellas Pharma Inc., Tsukuba lines used in this study were not authenticated in our laboratory Research Center has been awarded accreditation status by but were purchased from the providers of authenticated cell the Association for Assessment and Accreditation of Laboratory lines and stored at early passages in a central cell bank at Animal Care International. HCC827, NCI-H1975, A431, PC- Astellas Pharma Inc., with Mycoplasma testing performed using 9vec, and PC-9AXL cells were inoculated subcutaneously PCR. The experiments were conducted using low-passage cul- into the flank of male CAnN.Cg-Foxn1nu/CrlCrlj mice. A xeno- tures of these stocks. graft study using LU1868 cells, a human NSCLC patient-derived xenograft (PDX) model with EGFR L858R/T790M, was In vitro cell proliferation assays conducted at Crown Bioscience Inc. LU1868 cells were inocu- Cell viability was assessed using the CellTiter-Glo Luminescent lated subcutaneously into the flank of female BALB/c nude Cell Viability Assay (Promega). A detailed protocol is provided in mice. the Supplementary Materials and Methods. Mice were randomized and administered vehicle, naquoti- nib, erlotinib, or osimertinib at indicated doses (for details, see Immunoblotting analysis the figures for each experiment). Body weight and tumor Protein was extracted using Cell Lysis Buffer
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