Nat Commun auth.: group Fajas

CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer

Dorian V Ziegler 1Kanishka Parashar 1Lucia Leal-Esteban 1Jaime López-Alcalá 1 2Wilson Castro 3Nadège Zanou 4Laia Martinez-Carreres 1Katharina Huber 1Xavier Pascal Berney 1María M Malagón 2 5Catherine Roger 1Marie-Agnès Berger 6Yves Gouriou 6Giulia Paone 1Hector Gallart-Ayala 7George Sflomos 8Carlos Ronchi 8Julijana Ivanisevic 7Cathrin Brisken 8 9Jennifer Rieusset 6Melita Irving 3Lluis Fajas 10 11

Affiliations Expand

Abstract

The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4’s role in regulating PKA activity at MERCs. In this work, we highlight CDK4’s role in mitochondrial apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy.