1. Academic Validation
  2. Induction of resistance to neurotrophic tropomyosin-receptor kinase inhibitors by HMGCS2 via a mevalonate pathway

Induction of resistance to neurotrophic tropomyosin-receptor kinase inhibitors by HMGCS2 via a mevalonate pathway

  • Cancer Med. 2024 Jun;13(12):e7393. doi: 10.1002/cam4.7393.
Yasuhiro Kato 1 Masaru Matsumoto 1 Natsuki Takano 1 Mariko Hirao 1 Kuniko Matsuda 1 Takehiro Tozuka 1 Naomi Onda 1 Shinji Nakamichi 1 Susumu Takeuchi 1 Akihiko Miyanaga 1 Rintaro Noro 1 Akihiko Gemma 1 Masahiro Seike 1
Affiliations

Affiliation

  • 1 Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
Abstract

Introduction: A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs.

Method: To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon Cancer cells with a TPM3-NTRK1 rearrangement.

Result: Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone.

Conclusion: These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon Cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.

Keywords

HMGCS2; NTRK‐TKI; mevalonate pathway; resistance mechanism; statin.

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