AZD0364 Is a Potent and Selective ERK1/2 Inhibitor That Enhances Antitumor Activity in<i>KRAS</i>-Mutant Tumor Models when Combined with the MEK Inhibitor, Selumetinib

Flemington, Vikki; Davies, Emma; Robinson, David M.; Sandin, Linda C.; Delpuech, Oona; Zhang, Pei; Hanson, Lyndsey; Farrington, Paul; Bell, Sigourney; Falenta, Katarzyna; Gibbons, Francis D.; Lindsay, Nicola; Smith, Aaron; Wilson, Joanne; Roberts, Karen; Tonge, Michael; Hopcroft, Philip; Willis, Sophie E.; Roudier, Martine P.; Rooney, Claire; Coker, Elizabeth A.; Jaaks, Patricia; Garnett, Mathew J.; Jones, Clifford D.; Ward, Richard A.; Simpson, Iain; Cosulich, Sabina C.; Pease, J. Elizabeth; Smith, Paul D.

doi:10.1158/1535-7163.mct-20-0002

Cited by 19 publications

(26 citation statements)

References 39 publications

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“…The RAS-RAF-MEK1/2-ERK1/2 (RAS/MAPK) signalling pathway is frequently dysregulated in human cancers, often by mutations in BRAF or RAS genes and therefore is an important node for development of novel oncology compounds. In a recent publication, the ERK 1/2 inhibitor AZD0364 was profiled across different in vivo xenograft models [ 23 – 25 ]. Treatment of the non-small cell lung cancer (NSCLC) Calu-6 KRAS mutant xenograft model with AZD0364 at 50 mg/kg once daily (QD) for 21 days resulted in tumour regressions.…”

Section: Resultsmentioning

confidence: 99%

“…Treatment of the non-small cell lung cancer (NSCLC) Calu-6 KRAS mutant xenograft model with AZD0364 at 50 mg/kg once daily (QD) for 21 days resulted in tumour regressions. In comparison, the A549 NSCLC KRAS mutant xenograft model was less sensitive to the same dose of AZD0364 reaching only partial tumour growth inhibition (TGI) [ 23 ]. The purpose of this experiment was to use the Microformulator to determine if this difference in response of the 2 KRAS mutant xenografts to AZD0364 could be replicated in an in vitro system and, if so, to compare results to traditional fixed concentration bolus dosing.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, the growth of less sensitive A549 cell line was significantly inhibited by the fixed bolus dose of AZD0364, whereas the Microformulator PK dose only weakly inhibited the growth of A549 cells over the duration of the experiment ( Fig 3B–3D ). These data indicate that the differences in cell line sensitivity is more accurately reflected in Microformulator PK doses of AZD0364 than the manual fixed concentration of AZD0364, when compared to the Calu-6 and A549 xenografts reported in vivo [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

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A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models

et al. 2022

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Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compounds over multiweek experiments, both as monotherapy and drug combinations, comparing the effects on tumour cell efficacy in vitro with efficacy seen in in vivo xenograft models. In the first example, an ERK1/2 inhibitor was tested using fixed bolus dosing and Microformulator-replicated PK profiles, in 2 cell lines with different in vivo sensitivities. The Microformulator-replicated PK profiles were able to discriminate between cell line sensitivities, unlike the conventional fixed bolus dosing. In a second study, murine in vivo PK profiles of multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) and DNA-dependent protein kinase (DNA-PK) inhibitor combinations were replicated in a FaDu cell line resulting in a reduction in cell growth in vitro with similar rank ordering to the in vivo xenograft model. Additional PK/efficacy insight into theoretical changes to drug exposure profiles was gained by using the Microformulator to expose FaDu cells to the DNA-PK inhibitor for different target coverage levels and periods of time. We demonstrate that the Microformulator enables incorporating PK exposures into cellular assays to improve in vitro–in vivo translation understanding for early therapeutic insight.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models

et al. 2022

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“…Clinical studies are ongoing to examine its role in tumors harboring activating MAPK mutations as a single agent or in combination with other agents (NCT03698994, NCT04145297). Recently, the combination of AZD0364, a selective Erk1/2 inhibitor, and selumetinib has been shown to alleviate tumor progression in multiple xenograft models of KRAS-mutant NSCLC [139]. Similarly, Catalano et al showed that dual inhibition of MEK and Erk represented anti-tumor efficacy and blocked the emergence of drug resistance in an HRAS G12C -driven autochthonous sarcoma model.…”

Section: Erk Inhibitorsmentioning

confidence: 99%

Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy

Tatlı

Doğanay

2021

Molecules

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Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers.

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“…A novel molecule selectively targeting ERK, SCH772984, induced tumor regression in mouse xenograft models with KRAS or NRAS mutations [154]. AZD0364 exhibited dose-and time-dependent modulation of ERK1/2-dependent signaling to result in tumor regression in sensitive BRAFand KRAS-mutant xenografts [157,158]. Another similar small molecule, BVD523 (ulixertinib), exhibited antitumor activity for MEK-BRAF in concurrent or single targeting in resistant models in vitro or in vivo [156].…”

Section: Erk Inhibitionmentioning

confidence: 99%

Emerging strategies to target RAS signaling in human cancer therapy

et al. 2021

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RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRASG12C-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.

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AZD0364 Is a Potent and Selective ERK1/2 Inhibitor That Enhances Antitumor Activity inKRAS-Mutant Tumor Models when Combined with the MEK Inhibitor, Selumetinib

Cited by 19 publications

References 39 publications

A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models

A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models

Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy

Emerging strategies to target RAS signaling in human cancer therapy

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