NTRK1-G595R mutation and ERK activation in NTRKs-rearranged
1. Martin-Zanca D, Hughes SH, Barbacid M. A human oncogene
formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature. 1986;319(6056):743-748.
2. Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett. 2001;169(2):107-114.
3. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and
TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731-747.
4. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in
TRK fusion-positive cancers in adults and children. N Engl J Med.
2018;378(8):731-739.
5. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients
with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol.
2020;21(2):271-282.
6. Russo M, Misale S, Wei GE, et al. Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov. 2016;6(1):36-4 4.
7. Drilon A, Ou S-H, Cho BC, et al. Repotrectinib (TPX-0 005) is
a next-generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent- front mutations. Cancer Discov.
2018;8(10):1227-1236.
8. Zheng Z, Liebers M, Zhelyazkova B, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med.
2014;20(12):1479-1484.
9. Morikawa K, Walker SM, Nakajima M, Pathak S, Jessup JM, Fidler
IJ. Influence of organ environment on the growth, selection, and
metastasis of human colon carcinoma cells in nude mice. Cancer
Res. 1988;48(23):6863-6871.
10. Nishiyama A, Yamada T, Kita K, et al. Foretinib overcomes entrectinib resistance associated with the NTRK1 G667C mutation in
NTRK1 fusion-positive tumor cells in a brain metastasis model. Clin
Cancer Res. 2018;24(10):2357-2369.
11. Fukuda K, Takeuchi S, Arai S, et al. Epithelial-to-m esenchymal
transition is a mechanism of ALK inhibitor resistance in lung
cancer independent of ALK mutation status. Cancer Res.
2019;79(7):1658-1670.
12. Nanjo S, Nakagawa T, Takeuchi S, et al. In vivo imaging models of bone and brain metastases and pleural carcinomatosis
with a novel human EML4-ALK lung cancer cell line. Cancer Sci.
2015;106(3):244-252.
13. Takeuchi S, Fukuda K, Arai S, et al. Organ-s pecific efficacy of HSP90 inhibitor in multiple-o rgan metastasis model
of chemorefractory small cell lung cancer. Int J Cancer.
2016;138(5):1281-1289.
14. Niederst MJ, Engelman JA. Bypass mechanisms of resistance
to receptor tyrosine kinase inhibition in lung cancer. Sci Signal.
2013;6(294):re6.
15. Nazarian R, Shi H, Wang QI, et al. Melanomas acquire resistance to
B-R AF(V600E) inhibition by RTK or N-R AS upregulation. Nature.
2010;468(7326):973-977.
16. Cocco E, Schram AM, Kulick A, et al. Resistance to TRK inhibition mediated by convergent MAPK pathway activation. Nat Med.
2019;25(9):1422-1427.
17. Yano S, Yamada T, Takeuchi S, et al. Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired
tumors treated with TRK-TKIs.
The MAPK/ERK pathway, comprising the RAS/RAF/MEK/ERK
axis, plays a critical role in the survival and proliferation of various
tumor cells. We found that ERK activation was caused partly by
AREG-triggered EGFR activation in M3B cells. Interestingly, discernible ERK reactivation occurred even in the presence of repotrectinib and EGFR inhibitor gefitinib within 48 hours. The mechanism
by which ERK is reactivated remains unclear currently. There are
several possibilities, including the activation of receptor tyrosine
kinases other than EGFR, inhibition of negative regulators for the
MAPK pathway such as Sprouty (SPRY) proteins and dual-specificity
phosphatases (DUSPs).18 We aim to characterize the precise mechanism underlying ERK reactivation in future research.
The limitations of the present study are that only M3B cells were
analyzed as TRK inhibitor–resistant NTRK1-rearranged tumor cells. As
NTRKs-rearranged cancer is a rare disease, we were unable to obtain
other native tumor cell lines with NTRK1 rearrangement. Similarly, we
could not obtain clinical specimens from NTRKs-rearranged cancer
patients whose tumors acquired resistance to TRK inhibitors. Further
experiments with other NTRK1-rearranged tumor cells and clinical
specimens are warranted in future to delineate the clinical relevance
of our results obtained in the present study.
In conclusion, we demonstrated that resistant mutations, such as
NTRK1-G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib-resistant tumors and
thereby cause resistance to second-generation inhibitor repotrectinib.
These findings underscore the necessity for intensive examinations to
accurately characterize the governing resistance mechanism and implementing the appropriate combination treatment to surmount the
resistance.
AC K N OW L E D G E M E N T S
We thank Dr. Ryohei Katayama (Japanese Foundation for Cancer
Research) for kindly providing us with the Ba/F3_WT and Ba/F3_
G595R cells.
D I S C LO S U R E
Dr. Yano is an editorial board member of Cancer Science. All the
other authors have declared no conflicts of interest.
ORCID
Chiaki Suzuki https://orcid.org/0000-0002-3287-7857
Akihiro Nishiyama https://orcid.org/0000-0002-4805-9787
13497006, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cas.15354 by Cochrane Japan, Wiley Online Library on [15/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2334 resistance to tyrosine kinase inhibitors in a Japanese cohort. J
Thorac Oncol. 2011;6(12):2011-2017.
8. Lake D, Corrêa SA, Müller J. Negative feedback regulation of the
ERK1/2 MAPK pathway. Cell Mol Life Sci. 2016;73(23):4397-4 413.
S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found in the online
version of the article at the publisher’s website.
2335
How to cite this article: Suzuki C, Nishiyama A, Arai S, et al.
Inhibition of EGFR and MEK surmounts entrectinib resistance
in a brain metastasis model of NTRK1-rearranged tumor cells.
Cancer Sci. 2022;113:2323–2335. doi:10.1111/cas.15354
13497006, 2022, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cas.15354 by Cochrane Japan, Wiley Online Library on [15/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SUZUKI et al.
...
論文の公開元へ
