TY - JOUR
T1 - FGFR signaling as a candidate therapeutic target for cancers resistant to carbon ion radiotherapy
AU - Darwis, Narisa Dewi Maulany
AU - Nachankar, Ankita
AU - Sasaki, Yasushi
AU - Matsui, Toshiaki
AU - Noda, Shin Ei
AU - Murata, Kazutoshi
AU - Tamaki, Tomoaki
AU - Ando, Ken
AU - Okonogi, Noriyuki
AU - Shiba, Shintaro
AU - Irie, Daisuke
AU - Kaminuma, Takuya
AU - Kumazawa, Takuya
AU - Anakura, Mai
AU - Yamashita, Souichi
AU - Hirakawa, Takashi
AU - Kakoti, Sangeeta
AU - Hirota, Yuka
AU - Tokino, Takashi
AU - Iwase, Akira
AU - Ohno, Tatsuya
AU - Shibata, Atsushi
AU - Oike, Takahiro
AU - Nakano, Takashi
N1 - Funding Information:
Funding: This research was funded by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan for programs for Leading Graduate Schools, Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering. This research was also funded by Gunma University Heavy Ion Medical Center. This research was supported by JSPS KAKENHI Grant Number 221S0001.
Funding Information:
This research was funded by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan for programs for Leading Graduate Schools, Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering. This research was also funded by Gunma University Heavy Ion Medical Center. This research was supported by JSPS KAKENHI Grant Number 221S0001. This work was conducted under the following framework: Research Project with Heavy Ions at Gunma Heavy Ion Medical Center.
Publisher Copyright:
© 2019 by the authors.
PY - 2019/9/2
Y1 - 2019/9/2
N2 - Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.
AB - Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.
KW - Carbon ion radiotherapy
KW - FGFR
KW - LY2874455
KW - Next-generation sequencer
KW - Radiosensitization
KW - Somatic mutations
KW - Uterine cervical cancer
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U2 - 10.3390/ijms20184563
DO - 10.3390/ijms20184563
M3 - Article
C2 - 31540114
AN - SCOPUS:85072511256
SN - 1661-6596
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 18
M1 - 4563
ER -
