The spindle assembly checkpoint maintains genomic integrity. A key component is
tyrosine threonine kinase (TTK, also known as Mps1). TTK antagonism is hypothesized to cause
genomic instability and cell death. Interrogating The
Cancer Genome Atlas revealed high TTK expression in
lung adenocarcinomas and
squamous cell cancers versus the normal lung (P < 0.001). This correlated with an unfavorable prognosis in examined
lung adenocarcinoma cases (P = 0.007). TTK expression profiles in lung
tumors were independently assessed by
RNA in situ hybridization.
CFI-402257 is a highly selective TTK inhibitor. Its potent
antineoplastic effects are reported here against a panel of well-characterized murine and human
lung cancer cell lines. Significant antitumorigenic activity followed independent treatments of athymic mice bearing human
lung cancer xenografts (6.5 mg/kg, P < 0.05; 8.5 mg/kg, P < 0.01) and immunocompetent mice with syngeneic
lung cancers (P < 0.001).
CFI-402257 antineoplastic mechanisms were explored.
CFI-402257 triggered
aneuploidy and apoptotic death of
lung cancer cells without changing centrosome number. Reverse phase
protein arrays (RPPA) of vehicle versus CFI-402257-treated
lung cancers were examined using more than 300 critical growth-regulatory
proteins. RPPA bioinformatic analyses discovered
CFI-402257 enhanced MAPK signaling, implicating MAPK antagonism in augmenting TTK inhibitory effects. This was independently confirmed using genetic and pharmacologic repression of MAPK that promoted
CFI-402257 anticancer actions. TTK antagonism exerted marked
antineoplastic effects against
lung cancers and MAPK inhibition cooperated. Future work should determine whether
CFI-402257 treatment alone or with a MAPK inhibitor is active in the
lung cancer clinic.