Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer

Abstract

BackgroundPolo-like kinase 1 (Plk1) is a serine/threonine kinase that is a key regulator of multiple stages of mitotic progression. Plk1 is upregulated in many tumor types including colorectal cancer (CRC) and portends a poor prognosis. TAK-960 is an ATP-competitive Plk1 inhibitor that has demonstrated efficacy across a broad range of cancer cell lines, including CRC. In this study, we investigated the activity of TAK-960 against a large collection of CRC models including 55 cell lines and 18 patient-derived xenografts.MethodsFifty-five CRC cell lines and 18 PDX models were exposed to TAK-960 and evaluated for proliferation (IC50) and Tumor Growth Inhibition Index, respectively. Additionally, 2 KRAS wild type and 2 KRAS mutant PDX models were treated with TAK-960 as single agent or in combination with cetuximab or irinotecan. TAK-960 mechanism of action was elucidated through immunoblotting and cell cycle analysis.ResultsCRC cell lines demonstrated a variable anti-proliferative response to TAK-960 with IC50 values ranging from 0.001 to > 0.75 μmol/L. Anti-proliferative effects were sustained after removal of drug. Following TAK-960 treatment a highly variable accumulation of mitotic (indicating cell cycle arrest) and apoptotic markers was observed. Cell cycle analysis demonstrated that TAK-960 treatment induced G2/M arrest and polyploidy. Six out of the eighteen PDX models responded to single agent TAK-960 therapy (TGII< 20). The addition of TAK-960 to standard of care chemotherapy resulted in largely additive antitumor effects.ConclusionTAK-960 is an active anti-proliferative agent against CRC cell lines and PDX models. Collectively, these data suggest that TAK-960 may be of therapeutic benefit alone or in combination with other agents, although future work should focus on the development of predictive biomarkers and hypothesis-driven rational combinations.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4036-z) contains supplementary material, which is available to authorized users.

Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts

“…To evaluate the effects of GC1118 and cetuximab, tumor growth inhibition index (TGII) values were calculated from the average volume of the treated (Vt) and vehicle control (Vvc) groups using the following equation: TGII (%) = (Vt final -Vt initial)/(Vvc final -Vvc initial) × 100 [32]. For example, if the treatments resulted in no change in growth vs. vehicle-treated controls, TGII (%) = 100.…”

“…The start of dosing was defined as day 1, and tumor volumes and body weights were measured twice per week for 28–52 days, depending on the growth of each PDX. Tumor volume was calculated as (length × width 2 ) × 0.52 [32]. Relative tumor volume was normalized to the initial tumor volume on day 1.…”

“…A vehicle was administered intraperitoneally twice per week, and BEZ-235 was administered at 20 mg/kg (0.4 mg/mouse) orally five times per week [89]. TGII values was used for antitumor efficacy [32]. Mice were monitored daily for signs of toxicity.…”

The CINs of Polo-Like Kinase 1 in Cancer

“…These compounds disrupt PLK1 localization and show a phenotype of chromosome segregation defects and activation of the SAC [ 187 , 189 ], but these compounds are still early in development. TAK960, a pyrimidodiazepinone-based PLK1 inhibitor, acts as an ATP-competing reagent and is also in early developmental stage [ 190 , 191 ]. NMS-P937 is yet another new generation ATP-competitive PLK1 inhibitor, identified using structure-driven drug design on the pyrazoloquinazoline scaffold [ 192 , 193 ].…”

Emerging Strategies to Attack Polyploid Cancer Cells

“…Several classes of cancer therapy induce a polyploid cell population, including the clinically used taxanes such as docetaxel [24,38] and paclitaxel, [39], DNA damaging agents such as doxorubicin [40], radiation [14,41] and oncoprotein-targeting compounds [7,42]. This also includes targeted kinase inhibitory drugs that directly attack the mitotic machinery, such as Aurora kinase inhibitors [37,43] and Polo-like kinase inhibitors [44,45]. If cycles of polyploidization followed by reductive cell division fuel the progressive generation of aneuploidy, then a therapeutic that targets polyploid cancer cells may be a means to short circuit this cycling, attack the evolvability of the cancer genome and enhance the overall effectiveness of many currently used therapies.…”