2. Academic Validation
  3. Zoledronic acid enhances the efficacy of the MEK inhibitor trametinib in KRAS mutant cancers

Zoledronic acid enhances the efficacy of the MEK inhibitor trametinib in KRAS mutant cancers

  • Cancer Lett. 2019 Feb 1;442:202-212. doi: 10.1016/j.canlet.2018.10.022.
Xinyu Dai 1,  Hongwei Xia 2,  Sheng Zhou 1,  Qiulin Tang 3,  Feng Bi 4
Affiliations

Affiliations

  • 1 Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China; Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan Province, China.
  • 2 Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan Province, China. Electronic address: [email protected].
  • 3 Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan Province, China.
  • 4 Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China; Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan Province, China. Electronic address: [email protected].
PMID: 30429107 DOI: 10.1016/j.canlet.2018.10.022
Abstract

KRAS mutation is the most common type of mutation in human cancers. However, the direct pharmacological inhibition of KRAS has not been clinically successful. Trametinib (GSK1120212, Tram), a newer MEK Inhibitor, inhibits Ras signaling through mitogen-activated protein kinase (MAPK) cascade suppression. The effectiveness of Tram in clinical practice is limited in KRAS mutant tumors compared to that in BRaf mutant tumors. Here, we found that Tram treatment provoked feedback activation of upstream Ras, thus causing an induction of phosphorylated MEK (pMEK) and phosphorylated ERK (PERK) rebound in KRAS mutant tumors. This failure of persistent ERK inhibition led to drug resistance. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, disrupts the biological activity of Ras by inhibiting its isoprenylation. Surprisingly, ZA overcame Tram resistance, and augmented antitumor activity was observed in KRAS mutant tumors both in vitro and in vivo. Furthermore, ZA enhanced the effect of Tram partially through the mevalonate pathway. In summary, the combination of the two FDA-approved drugs Tram and ZA may represent a novel therapeutic strategy for the treatment of KRAS mutant cancers.

Keywords

MEK; Mevalonate pathway; RAS; Trametinib; Zoledronic acid.

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