Oncotarget

Research Papers:

MEK/CDK4,6 co-targeting is effective in a subset of NRAS, BRAF and 'wild type' melanomas

Christian Posch _, Martina Sanlorenzo, Jeffrey Ma, Sarasa T. Kim, Mitchell Zekhtser and Susana Ortiz-Urda

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Oncotarget. 2018; 9:34990-34995. https://doi.org/10.18632/oncotarget.26204

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Abstract

Christian Posch1,2,3, Martina Sanlorenzo2,4, Jeffrey Ma2, Sarasa T. Kim2, Mitchell Zekhtser2 and Susana Ortiz-Urda2

1Technical University of Munich, Department of Dermatology and Allergy, 80802 Munich, Germany

2University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, 94115 San Francisco, USA

3Faculty of Medicine, Sigmund Freud University, 1020, Vienna, Austria

4Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria

Correspondence to:

Christian Posch, email: [email protected]

Keywords: NRAS; CDK4; BRAF; MEK; melanoma

Received: August 01, 2018    Accepted: September 21, 2018    Published: October 09, 2018

ABSTRACT

Targeted therapy has become a cornerstone for the treatment of melanoma patients. Targeting NRAS function is particularly challenging. To date, only single MEK inhibitor treatment was able to show minimal clinical efficacy. The discovery that co-targeting of MEK and CDK4,6 has antitumor activity created excitement for patients and clinicians; however, it is largely unknown if only NRAS mutant patients might benefit from MEK/CDK4,6 blockade.

In this study we investigate response patterns of NRAS, BRAF mutant and ‘wild type’ melanoma cells in vitro and in vivo when challenged with inhibitors of MEK, CDK4,6 and the combination of both. Data revealed, that in vitro growth response patterns of cells treated with the MEK/CDK4,6 combination correspond to in vivo efficacy of MEK/CDK4,6 co-targeting in melanoma xenograft models. Strikingly, this was consistently observed in NRAS and BRAF mutant, as well as in ‘wild type’ melanoma cells. Additionally, cells displaying elevated p-Rb levels after single MEK inhibition, showed more effective growth reduction with MEK/CDK4,6 co-targeting compared to single MEK inhibitor treatment in vivo. Findings indicate that combined MEK/CDK4,6 inhibition could offer an effectively therapeutic modality in a subset of BRAF and NRAS mutant, as well as ‘wild type’ melanoma patients.


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