Investigational multitargeted kinase inhibitors in development for head and neck neoplasms

Abstract

Introduction: Despite advances in treatment, head and neck squamous cell carcinoma (HNSCC) survival rates remain stagnant. Current treatment is associated with significant toxicities and includes chemotherapy, radiation, surgery, and few targeted treatments. Targeted treatments, epidermal growth factor receptor (EGFR)-targeted agent, cetuximab, and immune checkpoint inhibitors, pembrolizumab and nivolumab, show improved toxicity profiles and modestly improved survival in select patients. An urgent need remains to identify novel targeted treatments for single-agent or combined therapy use.

Areas covered: Multitargeted kinase inhibitors are small molecule inhibitors with limited toxicity. This review will focus on early-stage investigations of multitargeted tyrosine kinase inhibitors (m-TKIs) (those that target at least two tyrosine kinases) for HNSCC. Preclinical and early trials investigating m-TKIs for various disease settings of HNSCC will be evaluated for efficacy, identification of significant biomarkers and potential for combination therapy.

Expert opinion: Few single agent m-TKIs have demonstrated efficacy in unselected HNSCC populations. The most promising clinical results have been obtained when m-TKIs are tested in combination with other therapies, including immunotherapy, or in mutation-defined subgroups of patients. The future success of m-TKIs will rely on identification, in preclinical models and clinical trials, of predictive biomarkers of response and mechanisms of innate and acquired resistance.

Keywords: Head and neck cancer; immunotherapy; multitargeted kinase inhibitors; squamous cell carcinoma; tyrosine-kinase inhibitors.

Figure 1:. Emerging investigated multi-targeted kinase inhibitors in head and neck squamous cell carcinoma.

Multi-target kinase inhibitors (m-TKIs) currently being tested in clinical trials target various molecular pathways. m-TKIs compete with ATP for binding to receptor tyrosine kinases to inhibit downstream signaling. This pictorial representation of common tumorigenic molecular pathways shows downstream signaling of epidermal growth factor receptor (EGFR) and HER family receptors, which activates the RAS/RAF/MEK/ERK pathways and PI3K/AKT/mTOR pathways, supporting tumor cell proliferation and survival. EGFR/HER kinase inhibitors include lapatinib, afatinib and poziotinib. Briefly, VEGFR, PDGFR, FGFR, MET, KIT and BCR-ABL activation also leads to downstream activation of a variety of molecular pathways including RAS/RAF/MEK/ERK, STAT and PI3K/AKT pathways resulting in proliferation, survival and, in some cases, angiogenesis. These pathways are inhibited in various combinations by several m-TKIs. AKT: v-AKT Murine thymoma viral oncogene; BCR-ABL: Breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog 1; ERK: Extracellular signal-regulated kinase; FGFR: Fibroblast growth factor receptor; HER: Human EGFR; KIT: Also called c-KIT tyrosine kinase; c-MET: Also called c-MET tyrosine kinase or HGF receptor; MEK: MAPK/ERK kinase; mTOR: Mammalian target of rapamycin; PDGFR: Platelet derived growth factor receptor; PI3K: Phosphatidylinositol-3-kinase; RAF: Rapidly accelerated fibrosarcoma kinase; RAS: Rat sarcoma protein; c-SRC: Sarcoma-family kinase; STAT: Signal transducer and activator of transcription; VEGFR: Vascular endothelial growth factor receptor.