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  3. Pharmacological induction of membrane lipid poly-unsaturation sensitizes melanoma to ROS inducers and overcomes acquired resistance to targeted therapy

Pharmacological induction of membrane lipid poly-unsaturation sensitizes melanoma to ROS inducers and overcomes acquired resistance to targeted therapy

  • J Exp Clin Cancer Res. 2023 Apr 19;42(1):92. doi: 10.1186/s13046-023-02664-7.
Ali Talebi # 1,  Vincent de Laat # 1,  Xander Spotbeen # 1,  Jonas Dehairs # 1,  Florian Rambow 2 3,  Aljosja Rogiers 4 5,  Frank Vanderhoydonc 1,  Lara Rizotto 6 7,  Mélanie Planque 8 9,  Ginevra Doglioni 8 9,  Sahar Motamedi 1,  David Nittner 10,  Tania Roskams 11,  Patrizia Agostinis 12,  Oliver Bechter 13,  Veerle Boecxstaens 14,  Marjan Garmyn 15,  Marie O'Farrell 16,  Alan Wagman 17,  George Kemble 16,  Eleonora Leucci 6 7,  Sarah-Maria Fendt 8 9,  Jean-Christophe Marine # 4 5,  Johannes V Swinnen # 18
Affiliations

Affiliations

  • 1 Department of Oncology, Laboratory of Lipid Metabolism and Cancer, LKI, KU Leuven, 3000, Leuven, Belgium.
  • 2 Department of Applied Computational Cancer Research, Institute for AI in Medicine (IKIM), University Hospital Essen, Essen, Germany.
  • 3 University of Duisburg-Essen, Essen, Germany.
  • 4 Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, 3000, Leuven, Belgium.
  • 5 Department of Oncology, Laboratory for Molecular Cancer Biology, KU Leuven, 3000, Leuven, Belgium.
  • 6 Department of Oncology, Laboratory for RNA Cancer Biology, LKI, KU Leuven, Leuven, Belgium.
  • 7 Department of Oncology, Trace PDX Platform, LKI, KU Leuven, Leuven, Belgium.
  • 8 Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, 3000, Leuven, Belgium.
  • 9 Department of Oncology, Laboratory of Cellular Metabolism and Metabolic Regulation, LKI, KU Leuven, 3000, Leuven, Belgium.
  • 10 Histopathology Expertise Center, VIB-KU Leuven Center for Cancer Biology, 3000, Leuven, Belgium.
  • 11 Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
  • 12 Department of Cellular and Molecular Medicine, VIB-KU Leuven Center for Cancer Biology, KU Leuven, Leuven, Belgium.
  • 13 LKI, Department of General Medical Oncology, Department of Oncology, University Hospitals Leuven, KU, Leuven, Belgium.
  • 14 Department of Oncology, KU Leuven and Department of Surgical Oncology, UZ Leuven, Leuven, Belgium.
  • 15 Department of Oncology and Dermatology, Laboratory of Dermatology, University Hospitals Leuven, University of Leuven, Leuven, Belgium.
  • 16 Sagimet Biosciences, 155 Bovet Rd, San Mateo, CA, 94402, USA.
  • 17 3-V Biosciences, Inc, 3715 Haven Ave, Menlo Park, CA, 94025, USA.
  • 18 Department of Oncology, Laboratory of Lipid Metabolism and Cancer, LKI, KU Leuven, 3000, Leuven, Belgium. [email protected].
  • # Contributed equally.
PMID: 37072838 DOI: 10.1186/s13046-023-02664-7
Abstract

Background: One of the key limitations of targeted Cancer therapies is the rapid onset of therapy resistance. Taking BRAF-mutant melanoma as paradigm, we previously identified the lipogenic regulator SREBP-1 as a central mediator of resistance to MAPK-targeted therapy. Reasoning that lipogenesis-mediated alterations in membrane lipid poly-unsaturation lie at the basis of therapy resistance, we targeted fatty acid synthase (FASN) as key player in this pathway to evoke an exquisite vulnerability to clinical inducers of Reactive Oxygen Species (ROS), thereby rationalizing a novel clinically actionable combination therapy to overcome therapy resistance.

Methods: Using gene expression analysis and mass spectrometry-based lipidomics of BRAF-mutant melanoma cell lines, melanoma PDX and clinical data sets, we explored the association of FASN expression with membrane lipid poly-unsaturation and therapy-resistance. Next, we treated therapy-resistant models with a preclinical FASN inhibitor TVB-3664 and a panel of ROS inducers and performed ROS analysis, lipid peroxidation tests and real-time cell proliferation assays. Finally, we explored the combination of MAPK inhibitors, TVB-3664 and arsenic trioxide (ATO, as a clinically used ROS-inducer) in Mel006 BRaf mutant PDX as a gold model of therapy resistance and assessed the effect on tumor growth, survival and systemic toxicity.

Results: We found that FASN expression is consistently increased upon the onset of therapy resistance in clinical melanoma samples, in cell lines and in Mel006 PDX and is associated with decreased lipid poly-unsaturation. Forcing lipid poly-unsaturation in therapy-resistant models by combining MAPK inhibition with FASN inhibition attenuated cell proliferation and rendered cells exquisitely sensitive to a host of ROS inducers. In particular, the triple combination of MAPK inhibition, FASN inhibition, and the clinical ROS-inducing compound ATO dramatically increased survival of Mel006 PDX models from 15 to 72% with no associated signs of toxicity.

Conclusions: We conclude that under MAPK inhibition the direct pharmacological inhibition of FASN evokes an exquisite vulnerability to inducers of ROS by increasing membrane lipid poly-unsaturation. The exploitation of this vulnerability by combining MAPK and/or FASN inhibitors with inducers of ROS greatly delays the onset of therapy resistance and increases survival. Our work identifies a clinically actionable combinatorial treatment for therapy-resistant Cancer.

Keywords

Lipid metabolism; Melanoma; Therapy resistance.

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