Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions

Yuka Kato, Kiichiro Ninomiya, Kadoaki Oohashi, Shuta Tomida, Go Makimoto, Hiromi Watanabe, Kenichiro Kudo, Shingo Matsumoto, Shigeki Umemura, Koichi Goto, Eiki Ichihara, Takashi Ninomiya, Toshio Kubo, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

Original languageEnglish
JournalCancer Science
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Epidermal Growth Factor Receptor
Lung
Protein-Tyrosine Kinases
Gene Fusion
Neoplasms
RNA Sequence Analysis
Non-Small Cell Lung Carcinoma
Lung Neoplasms
Up-Regulation
Cell Line
gefitinib
cabozantinib
crizotinib
Receptor Protein-Tyrosine Kinases
Epidermal Growth Factor
Heterografts
Therapeutics
Phosphorylation
Antibodies
Growth

Keywords

  • AXL
  • cabozantinib
  • HB-EGF
  • non-small lung cancer
  • ROS1 fusion genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{7db6b1d4183e4b93a96c7b992736bebb,
title = "Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions",
abstract = "The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.",
keywords = "AXL, cabozantinib, HB-EGF, non-small lung cancer, ROS1 fusion genes",
author = "Yuka Kato and Kiichiro Ninomiya and Kadoaki Oohashi and Shuta Tomida and Go Makimoto and Hiromi Watanabe and Kenichiro Kudo and Shingo Matsumoto and Shigeki Umemura and Koichi Goto and Eiki Ichihara and Takashi Ninomiya and Toshio Kubo and Akiko Sato and Katsuyuki Hotta and Masahiro Tabata and Shinichi Toyooka and Yoshinobu Maeda and Katsuyuki Kiura",
year = "2018",
month = "1",
day = "1",
doi = "10.1111/cas.13752",
language = "English",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions

AU - Kato, Yuka

AU - Ninomiya, Kiichiro

AU - Oohashi, Kadoaki

AU - Tomida, Shuta

AU - Makimoto, Go

AU - Watanabe, Hiromi

AU - Kudo, Kenichiro

AU - Matsumoto, Shingo

AU - Umemura, Shigeki

AU - Goto, Koichi

AU - Ichihara, Eiki

AU - Ninomiya, Takashi

AU - Kubo, Toshio

AU - Sato, Akiko

AU - Hotta, Katsuyuki

AU - Tabata, Masahiro

AU - Toyooka, Shinichi

AU - Maeda, Yoshinobu

AU - Kiura, Katsuyuki

PY - 2018/1/1

Y1 - 2018/1/1

N2 - The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

AB - The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

KW - AXL

KW - cabozantinib

KW - HB-EGF

KW - non-small lung cancer

KW - ROS1 fusion genes

UR - http://www.scopus.com/inward/record.url?scp=85053424481&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053424481&partnerID=8YFLogxK

U2 - 10.1111/cas.13752

DO - 10.1111/cas.13752

M3 - Article

JO - Cancer Science

JF - Cancer Science

SN - 1347-9032

ER -