Theranostics 2020; 10(5):2008-2028. doi:10.7150/thno.40971 This issue

Research Paper

Stapled peptide targeting the CDK4/Cyclin D interface combined with Abemaciclib inhibits KRAS mutant lung cancer growth

Celine Bouclier1,*, Matthieu Simon1,*, Guillaume Laconde1, Morgan Pellerano1, Sebastien Diot1, Sylvie Lantuejoul2, Benoit Busser2,3, Laetitia Vanwonterghem3, Julien Vollaire3, Véronique Josserand3, Baptiste Legrand1, Jean-Luc Coll3, Muriel Amblard1, Amandine Hurbin3,#, May C. Morris1,#✉

1. Institut des Biomolécules Max Mousseron, CNRS, UMR 5247, Université de Montpellier, Faculté de Pharmacie, 15, Av. Charles Flahault, 34093 Montpellier, France
2. CHU Grenoble Alpes, Université Grenoble Alpes, Grenoble, France
3. Institut pour l'Avancée des Biosciences, INSERM U1209, CNRS UMR-5309, Université Grenoble Alpes, Grenoble, France
* These authors contributed equally
# These authors contributed equally

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Citation:
Bouclier C, Simon M, Laconde G, Pellerano M, Diot S, Lantuejoul S, Busser B, Vanwonterghem L, Vollaire J, Josserand V, Legrand B, Coll JL, Amblard M, Hurbin A, Morris MC. Stapled peptide targeting the CDK4/Cyclin D interface combined with Abemaciclib inhibits KRAS mutant lung cancer growth. Theranostics 2020; 10(5):2008-2028. doi:10.7150/thno.40971. Available from https://www.thno.org/v10p2008.htm

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Abstract

Graphic abstract

CDK4/cyclin D kinase constitutes an attractive pharmacological target for development of anticancer therapeutics, in particular in KRAS-mutant lung cancer patients, who have a poor prognosis and no targeted therapy available yet. Although several ATP-competitive inhibitors of CDK4 have been developed for anticancer therapeutics, they suffer from limited specificity and efficacy.

Methods: As an alternative to ATP-competitive inhibitors we have designed a stapled peptide to target the main interface between CDK4 and cyclin D, and have characterized its physico-chemical properties and affinity to bind cyclin D1.

Results: We have validated a positive correlation between CDK4/cyclin D level and KRAS mutation in lung cancer patients. The stapled peptide enters cells rapidly and efficiently, and inhibits CDK4 kinase activity and proliferation in lung cancer cells. Its intrapulmonary administration in mice enables its retention in orthotopic lung tumours and complete inhibition of their growth when co-administered with Abemaciclib.

Conclusion: The stapled peptide targeting the main interface between CDK4 and cyclin D provides promising therapeutic perspectives for patients with lung cancer.

Keywords: CDK4, Stapled Peptide, Inhibitor, Lung cancer (NSCLC), KRAS mutation