Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma

Siwen Hu-Lieskovan; Stephen Mok; Blanca Homet Moreno; Jennifer Tsoi; Lidia Robert; Lucas Goedert; Elaine M. Pinheiro; Richard C. Koya; Thomas G. Graeber; Begoña Comin-Anduix; Antoni Ribas

doi:10.1126/scitranslmed.aaa4691

Research ArticleCancer

Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF^V600E melanoma

Siwen Hu-Lieskovan¹,
Stephen Mok¹,
Blanca Homet Moreno¹,²,
Jennifer Tsoi³,⁴,
Lidia Robert¹,
Lucas Goedert¹,
Elaine M. Pinheiro⁵,
Richard C. Koya¹,*,
Thomas G. Graeber³,⁴,⁶,
Begoña Comin-Anduix⁶,⁷ and
Antoni Ribas¹,⁴,⁶,⁷,†

¹Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
²Division of Translational Oncology, Carlos III Health Institute, Madrid 28029, Spain.
³Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA.
⁴Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.
⁵Merck Research Laboratories, Boston, MA 02115, USA.
⁶Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.
⁷Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, CA 90095, USA.

↵†Corresponding author. E-mail: aribas{at}mednet.ucla.edu

↵* Present address: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

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Science Translational Medicine 18 Mar 2015:
Vol. 7, Issue 279, pp. 279ra41
DOI: 10.1126/scitranslmed.aaa4691

Siwen Hu-Lieskovan

1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.

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Stephen Mok

1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.

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Blanca Homet Moreno

1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.

2Division of Translational Oncology, Carlos III Health Institute, Madrid 28029, Spain.

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Jennifer Tsoi

3Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA.

4Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.

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Lidia Robert

1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.

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Lucas Goedert

1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.

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Elaine M. Pinheiro

5Merck Research Laboratories, Boston, MA 02115, USA.

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Richard C. Koya

1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.

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Thomas G. Graeber

3Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA.

4Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.

6Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.

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Begoña Comin-Anduix

6Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.

7Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, CA 90095, USA.

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Antoni Ribas

1Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.

4Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.

6Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.

7Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, CA 90095, USA.

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For correspondence: aribas@mednet.ucla.edu

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Melanoma’s triple threat

Combination therapy is the favored approach to fight drug-resistant cancer. For BRAF-mutated melanoma, combining a BRAF inhibitor and checkpoint inhibitors was hoped to improve the antitumor response; however, an early clinical trial was stopped because of liver toxicity. Hu-Lieskovan et al. test the addition of MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors to this combination therapy in an effort to potentiate the MAPK inhibition of BRAF inhibitors while concurrently decreasing the toxicity. They show in a mouse model of BRAF^V600E-driven melanoma that triple therapy with BRAF and MEK inhibitors together with adoptive cell transfer (ACT) immunotherapy induced complete tumor regression in a manner consistent with immune activation. In addition, replacing ACT with anti-PD1 in the triple therapy had similar results, supporting the testing of MEK and BRAF inhibitions with various immunotherapies in patients with BRAF-mutated melanoma.

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Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF^V600E melanoma

Melanoma’s triple threat

Science Translational Medicine

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