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Open AccessCommunication

FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy

1
Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan
2
Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo 060-8556, Japan
3
Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan
4
Gunma University Heavy Ion Medical Center, Maebashi 371-8511, Japan
5
Gunma University Initiative for Advanced Research (GIAR), Maebashi 371-8511, Japan
*
Author to whom correspondence should be addressed.
These authors equally contributed to this work.
Int. J. Mol. Sci. 2019, 20(18), 4563; https://doi.org/10.3390/ijms20184563
Received: 22 August 2019 / Revised: 10 September 2019 / Accepted: 12 September 2019 / Published: 14 September 2019
(This article belongs to the Special Issue Counteracting Radioresistance Using the Optimization of Radiotherapy)
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. View Full-Text
Keywords: carbon ion radiotherapy; uterine cervical cancer; next-generation sequencer; somatic mutations; FGFR; radiosensitization; LY2874455 carbon ion radiotherapy; uterine cervical cancer; next-generation sequencer; somatic mutations; FGFR; radiosensitization; LY2874455
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Darwis, N.D.M.; Nachankar, A.; Sasaki, Y.; Matsui, T.; Noda, S.-E.; Murata, K.; Tamaki, T.; Ando, K.; Okonogi, N.; Shiba, S.; Irie, D.; Kaminuma, T.; Kumazawa, T.; Anakura, M.; Yamashita, S.; Hirakawa, T.; Kakoti, S.; Hirota, Y.; Tokino, T.; Iwase, A.; Ohno, T.; Shibata, A.; Oike, T.; Nakano, T. FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy. Int. J. Mol. Sci. 2019, 20, 4563.

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