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

Tatlı, Özge; Doğanay, Gizem Dinler

doi:10.3390/molecules26247561

Cited by 3 publications

(3 citation statements)

References 207 publications

(222 reference statements)

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“…We further detect the expression levels of downstream signaling molecules of Ras in xenografted tumors to elucidate the profound anti-cancer mechanism of licoricidin. It is well-known that the Raf/Mek/Erk cascade, which is one of the major Ras downstream signaling pathways, is involved in proliferation, apoptosis, cell cycle, invasion, migration, and metastasis of gastric cancer ( Magnelli et al, 2020 ; Zhou et al, 2020 ) and is considered to be the compelling target for Ras-driven cancer therapy ( Tatli and Dinler Doganay, 2021 ). In this study, in comparison with the control group, levels of active Ras-GTP are significantly reduced in tumors exposed to licoricidin, in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Licoricidin combats gastric cancer by targeting the ICMT/Ras pathway in vitro and in vivo

Bai

et al. 2022

Front. Pharmacol.

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Licoricidin, a type of isoflavonoid, is extracted from the root of Glycyrrhiza glabra. It has been widely proven that licoricidin possesses multiple biological activities, including anti-cancer effects and a powerful antimicrobial effect against Helicobacter pylori (H. pylori). However, the exact mechanism of licoricidin against gastric cancer remains unclear. In this study, we comprehensively explored the effects of licoricidin on MGC-803 gastric cancer cells in vitro and in vivo and further elucidated its mechanism of action. Our results revealed that licoricidin exhibited multiple anti-gastric cancer activities, including suppressing proliferation, inducing apoptosis, arresting the cell cycle in G0/G1 phase, and inhibiting the migration and invasion abilities of MGC-803 gastric cancer cells. In addition to this, a total of 5861 proteins were identified by quantitative proteomics research strategy of TMT labeling, of which 19 differential proteins (two upregulated and 17 downregulated) were screened out. Combining bioinformatics analyses and the reported roles in cancer progression of the 19 proteins, we speculated that isoprenyl carboxyl methyltransferase (ICMT) was the most likely target of licoricidin. Western blot assays and IHC assays subsequently proved that licoricidin significantly downregulated the expression of ICMT, both in MGC-803 cells and in xenograft tumors. Moreover, licoricidin effectively reduced the level of active Ras-GTP and blocked the phosphorylation of Raf and Erk, which may be involved in its anti-gastric cancer effects. In summary, we first demonstrated that licoricidin exerted favorable anti-gastric cancer activities via the ICMT/Ras pathway, which suggests that licoricidin, as a natural product, could be a novel candidate for the management of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Licoricidin combats gastric cancer by targeting the ICMT/Ras pathway in vitro and in vivo

Bai

et al. 2022

Front. Pharmacol.

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“…The mitogen-activated protein kinase, or RAS–RAF–MEK–ERK, pathway regulates cell proliferation, differentiation, and survival and is aberrantly activated in more than a third of all cancers and approximately 90% of cutaneous melanomas [ 1 ]. Several MEK inhibitors have been developed and have been evaluated in a variety of cancers, but focus has increasingly turned to the evaluation of combinatorial strategies because of limited single-agent efficacy [ 2 ]. Cobimetinib is a reversible inhibitor of MEK1 and MEK2 that is approved for use in combination with vemurafenib for the treatment of BRAF V600 -mutated locally advanced or metastatic melanoma [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Serous Retinopathy Associated with Cobimetinib: Integrated Safety Analysis of Four Studies

et al. 2022

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Introduction and Objective Serous retinopathy can be associated with MEK inhibitors, including cobimetinib. We present results of an integrated safety analysis to further characterize ocular functional and structural changes due to serous retinopathy. Methods Four studies evaluating cobimetinib at the approved dose and schedule in combination with other oncology drugs were included. Study CO39721 incorporated standardized ophthalmologic assessments to fully characterize serous retinopathy events over time and was the primary study for analysis. Supporting information was provided by studies GO28141, WO29479, and GO30182. Results In total, 655 patients received one or more doses of cobimetinib and comprised the safety-evaluable population. Overall, 117 patients (17.9%) had one or more serous retinopathy events, 24 (3.7%) had two or more events, and four (0.6%) had three or more events. Grade 3 events occurred in < 2.5% of patients. In CO39721, the median time to onset was 15 days (range 7–111); median time to resolution of first occurrence was 26 days (range 6–591 + days). Twelve of 25 patients (48.0%) recovered without a dose modification and 4/25 (16.0%) were recovered/recovering following a dose modification. The most frequent presentation of serous retinopathy was focal subretinal fluid on optical coherence tomography (62.8% of cases); in some instances (25.7% of cases), subretinal fluid was multifocal. There was no loss of visual function or visual acuity at serous retinopathy onset or resolution. Conclusions Results from this integrated safety analysis indicate that cobimetinib-associated serous retinopathy can be managed with or without a dose modification of cobimetinib at the discretion of the treating physician. No visual loss or permanent retinal damage was identified on comprehensive ophthalmologic assessments. Clinical Trial Registration ClinicalTrials.gov identifiers: NCT03178851, NCT01689519, NCT02322814, and NCT02788279. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-022-01248-2.

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“…However, even after selection by genetic aberration, only subgroups of included patients benefit from targeted treatment. Moreover, treatment response to signaling inhibitors is not always directly linked to mutations in the targeted pathways, as multiple mutations may accumulate in a tumor, allowing it to bypass inhibitor effects (Uitdehaag et al 2019 , 2014 ; Tatli and Dinler 2021 ). Therefore, there is a pressing need for an alternative, more accurate stratification for targeted therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification

Lieshout

Faria

Peppelenbosch

et al. 2022

Mol Med

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Background Cholangiocarcinoma is a rare but lethal cancer of the biliary tract. Its first-line treatment is currently restricted to chemotherapy, which provides limited clinical benefit. Kinase inhibitors targeting oncogenic intracellular signaling have changed the treatment paradigm of cancer over the last decades. However, they are yet to be widely applied in cholangiocarcinoma therapy. Cholangiocarcinoma has marked molecular heterogeneity, which complicates the discovery of new treatments and requires patient stratification. Therefore, we investigated whether a commercial kinome profiling platform could predict druggable targets in cholangiocarcinoma. Methods Kinase activity in patient-derived cholangiocarcinoma organoids, non-tumorous adjacent tissue-derived and healthy donor-derived intrahepatic cholangiocyte organoids was determined using the PamChip® phosphotyrosine kinase microarray platform. Kinome profiles were compared and correlated with RNA sequencing and (multi-)kinase inhibitor screening of the cholangiocarcinoma organoids. Results Kinase activity profiles of individual cholangiocarcinoma organoids are different and do not cluster together. However, growth factor signaling (EGFR, PDGFRβ) and downstream effectors (MAPK pathway) are more active in cholangiocarcinoma organoids and could provide potential druggable targets. Screening of 31 kinase inhibitors revealed several promising pan-effective inhibitors and compounds that show patient-specific efficacy. Kinase inhibitor sensitivity correlated to the activity of its target kinases for several inhibitors, signifying them as potential predictors of response. Moreover, we identified correlations between drug response and kinases not directly targeted by those drugs. Conclusions In conclusion, kinome profiling is a feasible method to identify druggable targets for cholangiocarcinoma. Future studies should confirm the potential of kinase activity profiles as biomarkers for patient stratification and precision medicine.

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

Cited by 3 publications

References 207 publications

Licoricidin combats gastric cancer by targeting the ICMT/Ras pathway in vitro and in vivo

Licoricidin combats gastric cancer by targeting the ICMT/Ras pathway in vitro and in vivo

Characterization of Serous Retinopathy Associated with Cobimetinib: Integrated Safety Analysis of Four Studies

Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification

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