GSK3 Alpha and Beta Are New Functionally Relevant Targets of Tivantinib in Lung Cancer Cells

Abstract

Tivantinib has been described as a potent and highly selective inhibitor of the receptor tyrosine kinase c-MET and is currently in advanced clinical development for several cancers including non-small cell lung cancer (NSCLC). However, recent studies suggest that tivantinib’s anticancer properties are unrelated to c-MET inhibition. Consistently, in determining tivantinib’s activity profile in a broad panel of NSCLC cell lines, we found that, in contrast to several more potent c-MET inhibitors, tivantinib reduces cell viability across most of these cell lines. Applying an unbiased, mass-spectrometry-based, chemical proteomics approach, we identified glycogen synthase kinase 3 (GSK3) alpha and beta as novel tivantinib targets. Subsequent validation showed that tivantinib displayed higher potency for GSK3α than for GSK3β and that pharmacological inhibition or simultaneous siRNA-mediated loss of GSK3α and GSK3β caused apoptosis. In summary, GSK3α and GSK3β are new kinase targets of tivantinib that play an important role in its cellular mechanism-of-action in NSCLC.

Integrated High Throughput Analysis Identifies GSK3 as a Crucial Determinant of p53-Mediated Apoptosis in Lung Cancer Cells

“…Thus, SEMA3A was not considered for subsequent experiments. In contrast, GSK3β inhibition, FYN inhibition and MET inhibition have been shown as promising strategies for combating cancer [35-37]. In our study, both FYN inhibition and MET inhibition were synthetic lethal with p53 activation in A549 cells (Table S6).…”

“…In our study, both FYN inhibition and MET inhibition were synthetic lethal with p53 activation in A549 cells (Table S6). Although not synthetic lethal with p53 activation, according to the genomic screening data, GSK3β is well known to act upstream of FYN kinase [38], and GSK3β inhibition by either siRNA or chemical inhibitors has been shown to decrease MET activity levels in A549 cells [35]. Moreover, among GSK3β, FYN and MET, only GSK3β has been shown to bind p53 [39, 40] and to modulate p53-mediated apoptosis [41, 42].…”

“…Moreover, among GSK3β, FYN and MET, only GSK3β has been shown to bind p53 [39, 40] and to modulate p53-mediated apoptosis [41, 42]. The absence of GSK3β from the abovementioned list of synthetic lethal nodes may due to the high level of cell death that results from GSK3β inhibition [35] or to reductions in the levels of both the active and the inhibitory forms of GSK3β via knockdown [43]. We investigated GSK3β in subsequent experiments.…”

Cabozantinib and Tivantinib, but Not INC280, Induce Antiproliferative and Antimigratory Effects in Human Neuroendocrine Tumor Cells in vitro: Evidence for ‘Off-Target' Effects Not Mediated by c-Met Inhibition

“…In other various tumor entities, resistance against EGFR inhibition or resistance against anti-VEGF therapy has been demonstrated to be mediated by compensatory upregulation of phosphorylated c-Met as an alternative signaling pathway. Inhibition of c-Met has been discussed as a potential target in combination therapies in order to overcome a c-Met-induced escape from EGFR inhibition [50,51,52,53,54,55,56] or escape from anti-VEGF therapy [31,57,58,59,60], as has been demonstrated in various tumor entities. These mechanisms have also been discussed for neuroendocrine tumors [19,20,21,31,61].…”

Discrete functions of GSK3α and GSK3β isoforms in prostate tumor growth and micrometastasis

“…However, several recent studies, including ours indicated that GSK3 inhibition directly impairs the cancer cell function in vitro, and growth and metastasis of multiple cancers in vivo such as prostate [13], pancreas [9, 10], oral [8], and ovarian [21]. Reports indicated the specific role of GSK3β isoform in pancreatic [7] and non-small cell lung cancer cells [22].…”