Intrinsic caspase-8 activation mediates sensitization of erlotinib-resistant tumor cells to erlotinib/cell-cycle inhibitors combination treatment

Abstract

Inhibitors of the tyrosine kinase activity of epidermal growth factor receptor, as erlotinib, have an established role in treating several cancer types. However, resistance to erlotinib, particularly in breast cancer cell lines, and erlotinib treatment-associated disorders have also been described. Also, methods and combination therapies that could reverse resistance and ameliorate non-desirable effects represent a clinical challenge. Here, we show that the ATP non-competitive CDK2/cyclin A inhibitor NBI1 sensitizes erlotinib-resistant tumor cells to the combination treatment (co-treatment) for apoptosis-mediated cell death. Furthermore, in erlotinib-sensitive cells, the effective dose of erlotinib was lower in the presence of NBI1. The analysis in the breast cancer MDA-MB-468 erlotinib-resistant and in lung cancer A549 cell lines of the molecular mechanism underlying the apoptosis induced by co-treatment highlighted that the accumulation of DNA defects and depletion of cIAP and XIAP activates the ripoptosome that ultimately activates caspases-8 and -10 and apoptosis. This finding could have significant implications for future treatment strategies in clinical settings.

Small-molecule SMAC mimetics as new cancer therapeutics

“…SMAC mimetic can also sensitize glioblastoma cells to temozolomide-induced apoptosis through promoting ripoptosome formation [138]. Notably, targeted drugs such as CDK2/cyclin A inhibitor TAT-NBI1 in combination with ERFR inhibitor erlotinib lead to the depletion of IAP proteins, and ultimately ripoptosome-mediated apoptosis in erlotinib-resistant breast tumor cells [139]. Therefore combining SMAC mimetics with standard-of-care chemotherapeutics and other targeted drugs holds clinical promise conceptually.…”

Role of CDK5/cyclin complexes in ischemia-induced death and survival of renal tubular cells

“…Both roscovitine 17 and TAT-NBI1 7,8 induced cell death in tumor cell lines. Then we first determined the sensitivity of the LLC-PK1 cell line to these compounds in order to define sublethal concentrations.…”

“…7,8 The cellular model we used was the I/R model developed from an epithelial cell line deriving from pig kidney proximal tubule cells (LLC-PK1). 9 In this cell model, cells are subjected to hypoxia (1% O 2 ) and hypercapnia (18% CO 2 ) for 24 h, and Ischemia reperfusion processes induce damage in renal tubules and compromise the viability of kidney transplants.…”

“…It has been previously proposed that cyclin-dependent kinases (CDK) participate in ischemia-induced neuronal death, 4 and that CDK inhibitors provide protection. 5 Here we report that the CDK inhibitors roscovitine 6 and TAT-NBI1 7,8 provide protection against cell death in a well-established ischemia/reperfusion (I/R) model in porcine renal tubular cells (LLC-PK1). 9 When analyzing the molecular mechanism, we found the protective effect required of CDK5.…”

Pharmacological cyclin dependent kinase inhibitors: Implications for colorectal cancer

“…Studies have identified a peptide termed NBI1 that acts as a non-competitive inhibitor with certain cyclins [56] . Other preclinical studies in cell models have garnered more information about this novel peptide [57] . Further studies must be done in order to fully understand the capabilities of this peptide and see if there is a potential for clinical application.…”