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Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis.

Publication ,  Journal Article
Allegrezza, MJ; Rutkowski, MR; Stephen, TL; Svoronos, N; Perales-Puchalt, A; Nguyen, JM; Payne, KK; Singhal, S; Eruslanov, EB; Tchou, J ...
Published in: Cancer Res
November 1, 2016

Targeted therapies elicit seemingly paradoxical and poorly understood effects on tumor immunity. Here, we show that the MEK inhibitor trametinib abrogates cytokine-driven expansion of monocytic myeloid-derived suppressor cells (mMDSC) from human or mouse myeloid progenitors. MEK inhibition also reduced the production of the mMDSC chemotactic factor osteopontin by tumor cells. Together, these effects reduced mMDSC accumulation in tumor-bearing hosts, limiting the outgrowth of KRas-driven breast tumors, even though trametinib largely failed to directly inhibit tumor cell proliferation. Accordingly, trametinib impeded tumor progression in vivo through a mechanism requiring CD8+ T cells, which was paradoxical given the drug's reported ability to inhibit effector lymphocytes. Confirming our observations, adoptive transfer of tumor-derived mMDSC reversed the ability of trametinib to control tumor growth. Overall, our work showed how the effects of trametinib on immune cells could partly explain its effectiveness, distinct from its activity on tumor cells themselves. More broadly, by providing a more incisive view into how MEK inhibitors may act against tumors, our findings expand their potential uses to generally block mMDSC expansion, which occurs widely in cancers to drive their growth and progression. Cancer Res; 76(21); 6253-65. ©2016 AACR.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

November 1, 2016

Volume

76

Issue

21

Start / End Page

6253 / 6265

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Pyrimidinones
  • Pyridones
  • Proto-Oncogene Proteins p21(ras)
  • Osteopontin
  • Oncology & Carcinogenesis
  • Neoplasms
  • Myelopoiesis
  • Myeloid Cells
  • Mutation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Allegrezza, M. J., Rutkowski, M. R., Stephen, T. L., Svoronos, N., Perales-Puchalt, A., Nguyen, J. M., … Conejo-Garcia, J. R. (2016). Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis. Cancer Res, 76(21), 6253–6265. https://doi.org/10.1158/0008-5472.CAN-16-1308
Allegrezza, Michael J., Melanie R. Rutkowski, Tom L. Stephen, Nikolaos Svoronos, Alfredo Perales-Puchalt, Jenny M. Nguyen, Kyle K. Payne, et al. “Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis.Cancer Res 76, no. 21 (November 1, 2016): 6253–65. https://doi.org/10.1158/0008-5472.CAN-16-1308.
Allegrezza MJ, Rutkowski MR, Stephen TL, Svoronos N, Perales-Puchalt A, Nguyen JM, et al. Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis. Cancer Res. 2016 Nov 1;76(21):6253–65.
Allegrezza, Michael J., et al. “Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis.Cancer Res, vol. 76, no. 21, Nov. 2016, pp. 6253–65. Pubmed, doi:10.1158/0008-5472.CAN-16-1308.
Allegrezza MJ, Rutkowski MR, Stephen TL, Svoronos N, Perales-Puchalt A, Nguyen JM, Payne KK, Singhal S, Eruslanov EB, Tchou J, Conejo-Garcia JR. Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis. Cancer Res. 2016 Nov 1;76(21):6253–6265.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

November 1, 2016

Volume

76

Issue

21

Start / End Page

6253 / 6265

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Pyrimidinones
  • Pyridones
  • Proto-Oncogene Proteins p21(ras)
  • Osteopontin
  • Oncology & Carcinogenesis
  • Neoplasms
  • Myelopoiesis
  • Myeloid Cells
  • Mutation