The landscape of tyrosine kinase inhibitors in sarcomas: looking beyond pazopanib

Abstract

Introduction: Tyrosine kinases are key mediators of intracellular signaling cascades and aberrations in these proteins have been implicated in driving oncogenesis through the dysregulation of fundamental cellular processes including proliferation, migration, and apoptosis. As such, targeting these proteins with small molecule tyrosine kinase inhibitors (TKI) has led to significant advances in the treatment of a number of cancer types.Areas covered: Soft tissue sarcomas (STS) are a heterogeneous and challenging group of rare cancers to treat, but the approval of the TKI pazopanib for the treatment of advanced STS demonstrates that this class of drugs may have broad utility against a range of different sarcoma histological subtypes. Since the approval of pazopanib, a number of other TKIs have entered clinical trials to evaluate whether their activity in STS matches the promising results seen in other solid tumors. In this article, we review the emerging role of TKIs in the evolving landscape of sarcoma treatment.Expert opinion: As our biological understanding of response and resistance of STS to TKIs advances, we anticipate that patient management will move away from a 'one size fits all' paradigm toward personalized, multi-line, and patient-specific treatment regimens where patients are treated according to the underlying biology and genetics of their specific disease.

Keywords: biomarkers; kinases; sarcomas; signal transduction; targeted therapy; tyrosine kinase inhibitors.

Figure 1.

Kinase selectivity maps. Kinome-wide profiling measuring the dissociation constant (K_d), inhibitory constant (IC₅₀), or percent of control (POC) of the TKIs discussed within the review. The K_d data for imatinib, sunitinib, sorafenib, axitinib, cediranib, nintedanib, crizotinib, and dasatinib were obtained from PMID: 22037378 [16]. The K_d for regorafenib was obtained from PMID: 27734608 [17]. The IC₅₀ for anlotinib and sitravatinib were obtained from PMID: 29446853 and PMID: 26675259, respectively [19,20]. The POC for larotrectinib was obtained from PMID: 24162815 [51]. Abbreviations: CK1; Casein kinase 1, TK; Tyrosine kinase, STE; Sterile kinase, RGC; Receptor guanylate cyclase, CMGC; Cyclin-dependent kinase, mitogen-activated protein kinase, glycogen synthase kinase, and cyclin-dependent-kinase-like kinases, PI3K; Phosphoinositide 3-kinase, TKL; Tyrosine kinase-like, AGC; Protein kinases A, G, and C, CAMK; Ca²⁺/calmodulin-dependent protein kinase.