Identification and evaluation of novel drug combinations of Aurora kinase inhibitor CCT137690 for enhanced efficacy in oral cancer cells

Abstract

Oral cancer is the most prevalent subtype of head and neck cancers and arises mainly from squamous cells of the oral cavity. Patients with advanced metastatic disease have poor overall survival resulting primarily from limited treatment options. Recent advances in the understanding of molecular basis of oral tumorigenesis provide an opportunity for identification and validation of new drug targets. The deregulated expression of the Aurora family of mitotic kinases, for example, has been associated with pathogenesis and poor prognosis in oral cancer. Here, we have evaluated the efficacy of the pan-Aurora inhibitor (CCT137690) alone and in combination with different chemotherapeutic and targeted drugs to identify its synergistic partners in oral cancer cell lines (ORL-48 and ORL-115). CCT137690 effectively inhibits Aurora kinases in both the cell lines and displays potent antiproliferative activity towards them. Prolonged treatment of these cells with CCT137690 results in abrogated mitotic spindle formation, misaligned chromosome attachment and polyploidy that ultimately leads to apoptotic cell death. We further identified that inhibitors of EGFR (gefitinib) and PI3-kinase (pictilisib) synergize with CCT137690 to inhibit the proliferation of the oral cancer cell lines. Moreover, we demonstrate that polyethylene glycol-based nanocapsules harboring combinations of CCT137690 with gefitinib or pictilisib inhibit the growth of oral cancer cell lines in 3D spheroid cultures and induce apoptosis that is comparable to free drug combinations. In conclusion, we have demonstrated the in vitro efficacy of CCT137690 in oral cancer cell lines, identified novel drug combinations with CCT137690 and synthesized nanocapsules containing these drug combinations for co-administration.

Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer

“…Additionally, PHA680632 [ 139 ], reversine [ 33 , 140 ], CCT129202 [ 141 ], CCT137690 [ 142 , 143 ], SNS-314 [ 144 ], quercetin [ 145 , 146 ] are pan-aurora kinase inhibitors that have been tested in pre-clinical studies. Furthermore, VX-680 [ 147 , 148 , 149 ] and BI 811283 [ 108 , 109 ] are pan-AURK inhibitors that have been studied in clinical trials.…”

“…In addition, VX-680 was shown to sensitize PC3 cells for treatment with doxorubicin [ 162 ]. Another pan-AURK inhibitor CCT137690 demonstrated synergistic anti-oral cancer activity when used in combination with EGFR inhibitor gefitinib or PI-3K inhibitor pictilisib [ 143 ]. Subsequently, several studies attempted combination therapies along with AURKB inhibition.…”

Identification and Characterization of Natural and Semisynthetic Quinones as Aurora Kinase Inhibitors

“…Aurora kinases play critical roles in mitosis, and abrogation of their function results in the inhibition of cell proliferation. , We, therefore, next sought to evaluate the antiproliferative activity of 11 quinones in 8 different cancer cell lines using a 3 day SRB proliferation assay. These cell lines include two acute myeloid leukemia (AML) cell lines (MOLM-13 and MV-4-11), one chronic myeloid leukemia (CML) cell line (K562), four breast cancer lines [two triple negative (BT-549 and CAL-51) and two nontriple negative breast cancer (MCF-7 and HCC1954)], and a colon cancer cell line (HCT116) (Table ).…”

Combination Therapy as a Promising Way to Fight Oral Cancer

“…Overexpression of Aurora B can induce tumor formation since it promotes chromosomal instability, and suppresses cell cycle inhibitor p21 Cip1 , and is associated with a poor outcome [ 142 ]. The combination of pan-aurora inhibitors with an EGFR mAb revealed additive inhibition of cell growth, even in cell lines resistant to Cetuximab, while a synergistic effect in ORL cell lines was reported for the combination with a TKI [ 138 , 143 ].…”