Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies

Abstract

Targeted therapies using small-molecule inhibitors (SMIs) are commonly used in metastatic renal cell cancer (mRCC) patients; patients often develop drug resistance and eventually succumb to disease. Currently, understanding of mechanisms leading to SMIs resistance and any identifiable predictive marker(s) are still lacking. We discovered that DAB2IP, a novel Ras-GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. Loss of DAB2IP in RCC cells enhances their sensitivities to growth factor stimulation and resistances to SMI (such as mammalian target of rapamycin (mTOR) inhibitors). Mechanistically, loss of DAB2IP results in the activation of extracellular signal-regulated kinase/RSK1 and phosphoinositide-3 kinase/mTOR pathway, which synergizes the induction of hypoxia-inducible factor (HIF)-2α expression. Consequently, elevated HIF-2α suppresses p21/WAF1 expression that is associated with resistance to mTOR inhibitors. Thus combinatorial targeting both pathways resulted in a synergistic tumor inhibition. DAB2IP appears to be a new prognostic/predictive marker for mRCC patients, and its function provides a new insight into the molecular mechanisms of drug resistance to mTOR inhibitors, which also can be used to develop new strategies to overcome drug-resistant mRCC.

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

“…40 DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1 87 Tumor suppressor DAB2IP in cancer A Bellazzo et al expression of HIF-2α in renal cell carcinoma cells. 49 Therefore, DAB2IP inactivation may promote an hypoxia-like response, with upregulation of HIF target genes and increased expression and activity of VEGF proteins, affecting the cancer cell and its microenvironment, and promoting tumor vascularization.…”

Targeting 3-phosphoinositide-dependent protein kinase 1 associated with drug-resistant renal cell carcinoma using new oridonin analogs

“…6 We also established several RCC cell lines (i.e., 786-0 KD and HK-2 KD) resistant to mTOR and tyrosine kinase inhibitors from our recent publication. 9 Using these two models for initial screening of 10 oridonin analogs (Figure 1a), we identified CYD-6-17 that is fused at C-1 and C-2 of the A-ring as compared with oridonin (Figure 1b) with enhanced anticancer potency than oridonin (Supplementary Figure 1). …”

“…31 Inhibitors that target PI3K isoforms and other major nodes in the pathway, including AKT and mTOR, reach certain clinical benefits, however, major issues remain, such as limited efficacy or development of resistance to therapies. Our previous studies 9, 20 demonstrated that inhibitors of AKT or mTOR only exhibited little or moderate efficacy to RCC cells. A novel inhibitor of AKT1–PDPK1 interaction is reported to efficiently restrict tumor growth in prostate cancer.…”

“…20 We also found the combination of mTOR and ERK inhibitors could cause a synthetic lethal of drug-resistant RCC. 9 Based on combination strategy, in this study, we attempt to search new agent with multiple targeting capability.…”

“…6 Among them, CYD-6-17 that is fused at C-1 and C-2 of the A-ring (Figure 1b), has a better potency and aqueous solubility 6 and no major side effect in animal, exhibited very high potency to RCC cells with IC 50 at nanomolar range. We recently unveiled molecular mechanism leading to targeted therapeutics resistance in a variety of RCC cell lines; 9 several have acquired resistant (e.g., ACHN from metastatic RCC and Sor001 from a patient resistant to sorafenib) and the others are genetically induced (such as HK-2 KD and 786-0 KD). By screening these cell lines, we noticed that CYD-6-17 appeared to be very potent with similar IC 50 at nanomolar range.…”