MAPK Reliance via acquired CDK4/6 inhibitor resistance in cancer

Renee De Leeuw, Christopher McNair, Matthew J. Schiewer, Neermala Poudel Neupane, Lucas J. Brand, Michael A. Augello, Zhen Li, Larry C. Cheng, Akihiro Yoshida, Sean M. Courtney, E. Starr Hazard, Gary Hardiman, Maha H. Hussain, J. Alan Diehl, Justin M Drake, Wm Kevin Kelly, Karen E. Knudsen

Research output: Contribution to journalArticle

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Abstract

Purpose: Loss of cell-cycle control is a hallmark of cancer, which can be targeted with agents, including cyclin-dependent kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G 1 –S cell-cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon. Experimental Design: In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer. Results: This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive in vitro and in vivo phenotypes, including proliferation, migration, and invasion. Integration of RNA sequencing analysis and phosphoproteomics profiling revealed rewiring of the kinome, with a strong enrichment for enhanced MAPK signaling across all resistance models, which resulted in aggressive in vitro and in vivo phenotypes and prometastatic signaling. However, CDK4/6 inhibitor–resistant models were sensitized to MEK inhibitors, revealing reliance on active MAPK signaling to promote tumor cell growth and invasion. Conclusions: In sum, these studies identify MAPK reliance in acquired CDK4/6 inhibitor resistance that promotes aggressive disease, while nominating MEK inhibition as putative novel therapeutic strategy to treat or prevent CDK4/6 inhibitor resistance in cancer.

Original languageEnglish (US)
Pages (from-to)4201-4214
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number17
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

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Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinase 4
Neoplasms
Mitogen-Activated Protein Kinase Kinases
Cell Cycle Checkpoints
RNA Sequence Analysis
Phenotype
Retinoblastoma
Research Design
Phosphotransferases
Breast Neoplasms

PubMed: MeSH publication types

  • Journal Article

Cite this

De Leeuw, R., McNair, C., Schiewer, M. J., Neupane, N. P., Brand, L. J., Augello, M. A., ... Knudsen, K. E. (2018). MAPK Reliance via acquired CDK4/6 inhibitor resistance in cancer. Clinical Cancer Research, 24(17), 4201-4214. https://doi.org/10.1158/1078-0432.CCR-18-0410

MAPK Reliance via acquired CDK4/6 inhibitor resistance in cancer. / De Leeuw, Renee; McNair, Christopher; Schiewer, Matthew J.; Neupane, Neermala Poudel; Brand, Lucas J.; Augello, Michael A.; Li, Zhen; Cheng, Larry C.; Yoshida, Akihiro; Courtney, Sean M.; Starr Hazard, E.; Hardiman, Gary; Hussain, Maha H.; Alan Diehl, J.; Drake, Justin M; Kevin Kelly, Wm; Knudsen, Karen E.

In: Clinical Cancer Research, Vol. 24, No. 17, 01.09.2018, p. 4201-4214.

Research output: Contribution to journalArticle

De Leeuw, R, McNair, C, Schiewer, MJ, Neupane, NP, Brand, LJ, Augello, MA, Li, Z, Cheng, LC, Yoshida, A, Courtney, SM, Starr Hazard, E, Hardiman, G, Hussain, MH, Alan Diehl, J, Drake, JM, Kevin Kelly, W & Knudsen, KE 2018, 'MAPK Reliance via acquired CDK4/6 inhibitor resistance in cancer', Clinical Cancer Research, vol. 24, no. 17, pp. 4201-4214. https://doi.org/10.1158/1078-0432.CCR-18-0410
De Leeuw R, McNair C, Schiewer MJ, Neupane NP, Brand LJ, Augello MA et al. MAPK Reliance via acquired CDK4/6 inhibitor resistance in cancer. Clinical Cancer Research. 2018 Sep 1;24(17):4201-4214. https://doi.org/10.1158/1078-0432.CCR-18-0410
De Leeuw, Renee ; McNair, Christopher ; Schiewer, Matthew J. ; Neupane, Neermala Poudel ; Brand, Lucas J. ; Augello, Michael A. ; Li, Zhen ; Cheng, Larry C. ; Yoshida, Akihiro ; Courtney, Sean M. ; Starr Hazard, E. ; Hardiman, Gary ; Hussain, Maha H. ; Alan Diehl, J. ; Drake, Justin M ; Kevin Kelly, Wm ; Knudsen, Karen E. / MAPK Reliance via acquired CDK4/6 inhibitor resistance in cancer. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 17. pp. 4201-4214.
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AU - De Leeuw, Renee

AU - McNair, Christopher

AU - Schiewer, Matthew J.

AU - Neupane, Neermala Poudel

AU - Brand, Lucas J.

AU - Augello, Michael A.

AU - Li, Zhen

AU - Cheng, Larry C.

AU - Yoshida, Akihiro

AU - Courtney, Sean M.

AU - Starr Hazard, E.

AU - Hardiman, Gary

AU - Hussain, Maha H.

AU - Alan Diehl, J.

AU - Drake, Justin M

AU - Kevin Kelly, Wm

AU - Knudsen, Karen E.

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N2 - Purpose: Loss of cell-cycle control is a hallmark of cancer, which can be targeted with agents, including cyclin-dependent kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G 1 –S cell-cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon. Experimental Design: In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer. Results: This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive in vitro and in vivo phenotypes, including proliferation, migration, and invasion. Integration of RNA sequencing analysis and phosphoproteomics profiling revealed rewiring of the kinome, with a strong enrichment for enhanced MAPK signaling across all resistance models, which resulted in aggressive in vitro and in vivo phenotypes and prometastatic signaling. However, CDK4/6 inhibitor–resistant models were sensitized to MEK inhibitors, revealing reliance on active MAPK signaling to promote tumor cell growth and invasion. Conclusions: In sum, these studies identify MAPK reliance in acquired CDK4/6 inhibitor resistance that promotes aggressive disease, while nominating MEK inhibition as putative novel therapeutic strategy to treat or prevent CDK4/6 inhibitor resistance in cancer.

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