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| Status |
Public on Mar 10, 2023 |
| Title |
Induction of resistance to NTRK inhibitors via mevalonate pathway by HMGCS2 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Paretal KM12 and NTRK inhibitor resistant cells established from KM12 in our laboratory was compared to search for and analyze significant factors related to resistance mechanism. To investigated the mechanism of resistance to NTRK-TKI, we establish resistant cells to three type NTRK-TKIs (Larotrectinib, Entrectinib and Selitrectinib) by step -wise methods using KM12 with TPM5-NTRK1 rearrangement for 6 months. (KM12-LR, KM12-ER and KM12-SR) 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) over expression was observed commonly in three resistance cells. Lower expression of SREBP2 and PPARĪ± in two cells (KM12-ER and KM12-SR) in which HMGCS2 was more overexpressed than parental KM12 and KM12-LR.
In resistant cells, knockdown of HMGCS2 using small interfering RNA improved NTRK-TKIs sensitivity, but further treatment with mevalonolactone after knockdown HMGCS2 reintroduced NTRK-TKIs resistance. In addition, simvastatin and silibinin had synergic effect with NTRK-TKIs to resistant cells and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin against KM12. These results suggested that HMGCS2 overexpression induces resistance to NTRK-TKI via the mevalonate pathway. In addition, statin inhibited mevalonate pathway may be useful for overcoming this mechanism resistance.
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| Overall design |
We established resistance cells to three types NTRK inhibitor using KM12.We analyzed differences RNA expression between parental cell and three resistant cells for RNA extraction and hybridization on Affymetrix microarrays.
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| Contributor(s) |
Seike M, Matsumoto M |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Feb 21, 2023 |
| Last update date |
Mar 12, 2023 |
| Contact name |
Yasuhiro Kato |
| E-mail(s) |
y-kato@nms.ac.jp
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| Organization name |
Nippon Medical School
|
| Department |
Pulmonary Medicine and Oncology
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| Street address |
Sendagi 1-1-5
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| City |
Tokyo |
| State/province |
Bunkyo Ku |
| ZIP/Postal code |
1138603 |
| Country |
Japan |
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| Platforms (1) |
| GPL16686 |
[HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array [transcript (gene) version] |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA937158 |
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