From Bench to Bedside: A Team's Approach to Multidisciplinary Strategies to Combat Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in more than 71,000 patients each year in the United States, with nearly 16,000 associated deaths. One significant hurdle in the treatment of HNSCC is acquired and intrinsic resistance to existing therapeutic agents. Over the past several decades, the University of Wisconsin has formed a multidisciplinary team to move basic scientific discovery along the translational spectrum to impact the lives of HNSCC patients. In this review, we outline key discoveries made throughout the years at the University of Wisconsin to deepen our understanding of therapeutic resistance in HNSCC and how a strong, interdisciplinary team can make significant advances toward improving the lives of these patients by combatting resistance to established therapeutic modalities. We are profoundly grateful to the many scientific teams worldwide whose groundbreaking discoveries, alongside evolving clinical paradigms in head and neck oncology, have been instrumental in making our work possible.

Keywords: Axl; EGFR; HNSCC; MerTK; TAMs; cetuximab; resistance.

Figure 1

University of Wisconsin/City of Hope team: discoveries through the years.

Figure 2

RTKs’ role in therapeutic resistance and HNSCC progression. (A) In the context of chronic treatment, HNSCC can acquire resistance to cetuximab when (a) transphosphorylation of EGFR and Axl activates proliferation and survival pathways [61,66], (b) Axl activates c-Abl signaling through Y821 to inhibit apoptosis [67], (c) increased levels of EGF in the cytoplasm lead to SFK-mediated translocation of EGFR to the nucleus (nEGFR) via Y1101 [38,39,42,43], (d) decreased lysosomal degradation of EGFR and HER family members leads to persistent membrane expression [21], and (e) transphosphorylation of membrane-bound EGFR and HER2 or HER3 leads to activation of RAS, RAF, MEK, MAPK, and AKT pathways to promote tumor cell proliferation and survival. (B) Tumor-bound Axl and MerTK have been implicated in promoting tumor progression, and we found that (f) targeting Axl alone results in increased MerTK expression, leading to P70S6, RAF, and AKT activation and tumor progression [68], and (g) AKT activation can be turned off by targeting both Axl and MerTK with the dual inhibitor INCB081776 [71]. Furthermore, (h) genetic knockout of Axl can switch the TIME from cold to hot, leading to reduced tumor growth both in vitro and in vivo.