A ‘futile’ fatty acid cycle as central mediator and exploitable target in cancer resistance to molecular targeted therapy

With 14 million new cases and 8 million deaths annually, cancer remains one of the major health challenges. To improve the efficacy of cancer treatment while minimizing side effects, there is a strong movement towards molecular targeted approaches, usually targeting a mutant signaling protein specifically in cancer cells. One of the major challenges related to targeted treatments is the ease with which tumors escape therapies, despite an initial favorable response. This is largely related to the redundancy of signaling proteins in the proximal part of most signaling pathways, allowing ample opportunity for therapy escape. This highlighting the urgent need for identifying common downstream pathways as potential targets for novel therapeutic approaches that can more stably overcome therapy resistance. Taking the resistance of malignant melanoma to inhibitors targeting activating mutations in BRAF (such as vemurafenib), as a paradigm, solid preliminary evidence from our team indicates that altered lipid metabolism, and particularly an apparent ‘futile’ cycle of fatty acid synthesis and fatty acid degradation lies at the heart of this resistance. Here, using both in vitro and in vivo models as well as cutting edge technologies, including lipidomics, metabolomics and fluxomics, we aim to further establish this concept, to study its underlying mechanisms and roles and to ultimately explore its potential for combinatorial approaches to more stably overcome therapy resistance.