AMBRA1 and FAK1: crosstalking for improved targeted therapy in melanoma

Luca Di Leo; Daniela De Zio

doi:10.1080/23723556.2021.1949955

AMBRA1 and FAK1: crosstalking for improved targeted therapy in melanoma

Mol Cell Oncol. 2021 Jul 13;8(4):1949955. doi: 10.1080/23723556.2021.1949955. eCollection 2021.

Authors

Luca Di Leo¹, Daniela De Zio¹

Affiliation

¹ Melanoma Research Team, Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.

Abstract

Through genetically engineered mouse models of melanoma, we identified Autophagy/beclin 1 regulator 1 (Ambra1) as novel tumor-suppressor in melanoma. In these settings, loss of Ambra1 associated with the hyperactivation of focal adhesion kinase 1 (Fak1) signaling, the inhibition of which resulted in reduced tumor growth and invasiveness. We therefore propose FAK1 inhibition for current melanoma therapy in AMBRA1-low tumors.

Abbreviations: AKT, serine/threonine kinase 1; AMBRA1, autophagy/beclin 1 regulator 1; BRAF, v-raf murine sarcoma viral oncogene homolog; BRAFi, BRAF inhibitor; CCLE, Cancer Cell Line Encyclopedia;g ESTDAB, European Searchable Tumor Line Database; FAK1, focal adhesion kinase 1; FAKi, FAK1 inhibitor; LMC, Leeds Melanoma Cohort; MEK, MAPK/ERK kinase; PP2A, protein phosphatase 2A; PTEN, phosphatase and tensin homolog; TCGA-SKCM, The Cancer Genome Atlas - Skin Cutaneous Melanoma; YAP, yes-associated protein 1.

Keywords: AMBRA1; FAK1; melanoma; metastasis; therapy; tumor growth.

Grants and funding

This work has been supported by the Danish Cancer Society [KBVU R204-A12424]; LEO Fondet [LF-OC-19-000004]; Melanoma Research Alliance young investigator grant [MRA 620385].