Abstract

   Anti-epidermal growth factor receptor (EGFR) therapy (cetuximab) shows
   a limited clinical benefit for patients with locally advanced or
   recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), due
   to the frequent occurrence of secondary resistance mechanisms. Here we
   report that cetuximab-resistant HNSCC cells display a peroxisome
   proliferator-activated receptor alpha (PPARα)-mediated lipid metabolism
   reprogramming, with increased fatty acid uptake and oxidation
   capacities, while glycolysis is not modified. This metabolic shift
   makes cetuximab-resistant HNSCC cells particularly sensitive to a
   pharmacological inhibition of either carnitine palmitoyltransferase 1A
   (CPT1A) or PPARα in 3D spheroids and tumor xenografts in mice.
   Importantly, the PPARα-related gene signature, in human clinical
   datasets, correlates with lower response to anti-EGFR therapy and poor
   survival in HNSCC patients, thereby validating its clinical relevance.
   This study points out lipid metabolism rewiring as a non-genetic
   resistance-causing mechanism in HNSCC that may be therapeutically
   targeted to overcome acquired resistance to anti-EGFR therapy.

   Subject terms: Cancer metabolism, Head and neck cancer
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   Resistance to anti-EGFR therapy is a clinical issue for patients with
   advanced head and neck cancers. Here, the authors show that
   therapy-resistant cancer cells enhance fatty acid metabolism, which can
   be therapeutically targeted by inhibiting peroxisome
   proliferator-activated receptor alpha (PPARα).

Introduction

   Head and neck squamous cell carcinoma (HNSCC) afflicts about 700,000
   patients annually and is the sixth most common cancer worldwide^[82]1.
   HNSCC is often diagnosed at late stages, with loco-regionally advanced
   diseases for which treatment remains a clinical challenge^[83]2,[84]3.
   Indeed, despite aggressive multimodal therapeutic interventions
   including surgery, radiation therapy with or without concomitant
   chemotherapy, more than half of HNSCC patients experience loco-regional
   or distant relapse^[85]4. While immunotherapy has recently been
   implemented for patients with recurrent/metastatic HNSCC exhibiting
   programmed cell death ligand 1 (PD-L1) expression^[86]5, anti-epidermal
   growth factor receptor (EGFR) therapy remains the standard of care for
   PD-L1-negative advanced HNSCC as well as one therapeutic option for
   PD-L1-positive tumors that progress after immunotherapy
   treatment^[87]6. EGFR overexpression is observed in 90% of HNSCC^[88]7
   and it is associated with poor prognosis and resistance to radiation
   therapy and chemotherapy^[89]8,[90]9. However, the clinical efficacy of
   anti-EGFR monoclonal antibodies (e.g. cetuximab) is strongly limited by
   either intrinsic resistance or the development of acquired drug
   resistance after an initial tumor response, and most patients relapse
   within few months. Moreover, no validated treatment options exist for
   the patients who progress after anti-EGFR therapy, indicating an unmet
   clinical need. Unlike other cancer types (e.g. colorectal cancers with
   RAS/BRAF mutations or lung cancers with EGFR mutations), alterations in
   genes from the EGFR-regulated signaling pathways are extremely rare in
   HNSCC and they have not been clearly associated with the clinical
   response to anti-EGFR therapy^[91]10–[92]12. In this context,
   understanding resistance-supporting non-genetic causes is a critical
   challenge to improve the outcome of HNSCC patients receiving anti-EGFR
   targeted therapy. To date, several mechanisms of acquired resistance to
   cetuximab have already been identified in HNSCC patients^[93]13,[94]14.
   They are very diverse, likely due to the inter-patient heterogeneity as
   well as the influence of the tumor microenvironment and anatomic
   location^[95]15.

   Dysregulated cellular metabolism is a common hallmark of cancer, and it
   has emerged as an important factor that contributes to disease
   progression and clinical relapse in cancer patients, including
   HNSCC^[96]16,[97]17. Although it is well established that metabolic
   preferences in cancer cells can continuously evolve to fulfil their