Therapeutic sensitivity to Rac GTPase inhibition requires consequential suppression of mTORC1, AKT, and MEK signaling in breast cancer

Hampsch, Riley A.; Shee, Kevin; Bates, Darcy; Lewis, Lionel D.; Désiré, Laurent; Leblond, Bertrand; Demidenko, Eugene; Stefan, Kurtis; Huang, Yina H.; Miller, Todd W.

doi:10.18632/oncotarget.15586

Cited by 38 publications

(33 citation statements)

References 52 publications

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“…The model was able to fit all observations prior to 6 h, with a little overprediction from this time up to 12 h. Probably, the overprediction in the terminal phase of the C p -time profile justifies the slight difference between predicted (2.13 mL/min) and observed (2.15 mL/min) systemic plasma clearance. The rapid elimination of MBQ-167 from plasma, with a predicted elimination half-life ( t 1/2 ) of 2.98 h after IP administration of 10 mg/kg BW, is consistent with other reports of Rac inhibitors like EHop-016 or EHT1864, with t 1/2 values of 5.73 h [ 30 ] and 1.65 h [ 33 ], respectively. Predicted plasma exposition PK parameters AUC 0-t and C max were remarkably close to that observed, with fold errors of 1.09 and 0.99, respectively, showing the optimal prediction performance of the model.…”

Section: Discussionsupporting

confidence: 89%

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

et al. 2020

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MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim of this study is to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model of MBQ-167 to predict tumor growth inhibition following intraperitoneal (IP) administration in mice bearing Triple Negative and HER2+ mammary tumors. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the Simcyp V19 Animal Simulator. Our developed PBPK framework adequately describes the time course of MBQ-167 in each of the mouse tissues (e.g., lungs, heart, liver, kidneys, spleen, plasma) and tumor, since the predicted results were consistent with the experimental data. The developed PBPK-PD model successfully predicts tumor shrinkage in HER2+ and triple-negative breast tumors after the intraperitoneal administration of 1 and 10 mg/kg body weight (BW) dose level of MBQ-167 three times a week. The findings from this study suggest that MBQ-167 has a higher net effect and potency inhibiting Triple Negative mammary tumor growth compared to HER2+ and that liver metabolism is the major route of elimination of this drug.

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Section: Discussionsupporting

confidence: 89%

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

et al. 2020

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“…Certainly, side effects of EHT1864 are still incompletely understood, so that its tolerability needs to be evaluated. At least in animal models, severe side effects of EHT1864 were not reported following administration in vivo . However, in vivo data for EHT1864 are still limited.…”

Section: Discussionmentioning

confidence: 99%

New strategies for inhibition of non‐adrenergic prostate smooth muscle contraction by pharmacologic intervention

Gratzke

Wang

et al. 2019

The Prostate

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Background Inhibition of prostate smooth muscle contraction by α1‐adrenoceptor antagonists (α1‐blockers) is a first‐line medical treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Increased smooth muscle tone in the hyperplastic prostate may drive urethral obstruction, resulting in bladder outlet obstruction and voiding symptoms. However, efficacy of α1‐blockers is limited, as non‐adrenergic mediators including endothelin‐1 and thromboxane A2 (TXA2) increase prostate smooth muscle tension in parallel to α1‐adrenoceptors. This may maintain urethral obstruction despite therapy with α1‐blockers. Consequently, future treatment options with higher efficacy need to target α1‐adrenergic and non‐adrenergic contractions simultaneouly. Recently, several compounds were reported to inhibit adrenergic or neurogenic prostate contractions, however, their effects on non‐adrenergic contraction are unknown. Here, we examined effects of inhibitors for Rac‐GTPase, Src family kinases (SFKs), and p21‐activated kinases (PAKs) on non‐adrenergic prostate contractions. Methods Prostate tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath. Viability of cultured stromal cells was assessed by CCK‐8 assay. Results Inhibition of α1‐adrenergic contractions by Rac inhibitors EHT1864 (100 μM) and NSC23766 (100 μM), and SFK inhibitors AZM475721 (10 μM) and PP2 (10 μM) was confirmed by inhibition of methoxamine‐induced contractions. No effects of the PAK inhibitors FRAX486 (30 μM) and IPA3 (300 μM) on α1‐adrenergic contraction were confirmed by absent effects on methoxamine‐inuced contractions. EHT1864 caused inhibition of endothelin‐1‐ and U46619‐induced contractions. EHT1864 reduced the viability of stromal cells concentration‐ and time‐dependently. EHT1864 attenuated KCl‐induced contractions of prostate strips only slightly, so that toxic effects may not account alone for inhibition of agonist‐induced contractions. NSC23766 inhibited U46619‐induced contractions, but not endothelin‐1‐induced contractions. AZM475271 had no effects on endothelin‐1‐ or U46619‐induced contractions, while PP2 inhibited U46619‐ but not endothelin‐1‐induced contractions. FRAX486 caused inhibition of U46619‐induced contractions. IPA3 inhibited U46619‐, but not endothelin‐1‐induced contractions. Conclusions Of all six inhibitors, EHT1864 seems to be most promising from a translational point of view, as it inhibited TXA2‐ and endothelin‐1‐induced besides α1‐adrenergic prostate contractions. This reflects divergent pharmacologic profiles of EHT1864 and NSC23766, although both are Rac‐GTPase inhibitors. In vivo, urodynamic effects of EHT1864 and possibly of FRAX486 may exceed those of α1‐blockers.

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“…Numerous studies have implicated Rac/PAK activities with the maintenance of mesenchymal stem cell-like populations in epithelial cancers; and thus, therapy resistance (Zhao et al, 2011;Ong et al, 2013;Zhu et al, 2015;Goel et al, 2016;Huynh et al, 2016;Aboukameel et al, 2017;Lai et al, 2017;Morrison Joly et al, 2017;Cardama et al, 2018;Goka et al, 2019). Specifically in breast cancer, Rac/Cdc42/PAK signaling is implicated with therapy resistance of HER2-type (Wang et al, 2006;Ebi et al, 2013;Laurin et al, 2013;Dokmanovic et al, 2014;Desai et al, 2016;Hampsch et al, 2017), triple negative (De et al, 2017), and ER(+) cancers (Cai et al, 2003;Gonzalez et al, 2017). TCGA data show that Rac1 or PAK1 overexpression is associated with malignant breast cancer and significantly diminishes HER2 type patient survival within 10 years following diagnosis (Fang et al, 2016).…”

Section: Rac/cdc42 Inhibitors In Therapy Resistancementioning

confidence: 99%

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maldonado

Medina

Velázquez

et al. 2020

Front. Cell Dev. Biol.

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The Rho family GTPases Rho, Rac, and Cdc42 have emerged as key players in cancer metastasis, due to their essential roles in regulating cell division and actin cytoskeletal rearrangements; and thus, cell growth, migration/invasion, polarity, and adhesion. This review will focus on the close homologs Rac and Cdc42, which have been established as drivers of metastasis and therapy resistance in multiple cancer types. Rac and Cdc42 are often dysregulated in cancer due to hyperactivation by guanine nucleotide exchange factors (GEFs), belonging to both the diffuse B-cell lymphoma (Dbl) and dedicator of cytokinesis (DOCK) families. Rac/Cdc42 GEFs are activated by a myriad of oncogenic cell surface receptors, such as growth factor receptors, G-protein coupled receptors, cytokine receptors, and integrins; consequently, a number of Rac/Cdc42 GEFs have been implicated in metastatic cancer. Hence, inhibiting GEF-mediated Rac/Cdc42 activation represents a promising strategy for targeted metastatic cancer therapy. Herein, we focus on the role of oncogenic Rac/Cdc42 GEFs and discuss the recent advancements in the development of Rac and Cdc42 GEF-interacting inhibitors as targeted therapy for metastatic cancer, as well as their potential for overcoming cancer therapy resistance.

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Therapeutic sensitivity to Rac GTPase inhibition requires consequential suppression of mTORC1, AKT, and MEK signaling in breast cancer

Cited by 38 publications

References 52 publications

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

New strategies for inhibition of non‐adrenergic prostate smooth muscle contraction by pharmacologic intervention

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

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