Metabolic Adaptations to MEK and CDK4/6 Cotargeting in Uveal Melanoma

Teh, Jessica L.F.; Purwin, Timothy J.; Han, Anna; Chua, Vivian; Patel, Prem; Baqai, Usman; Liao, Connie; Bechtel, Nelisa; Sato, Takami; Davies, Michael A.; Aguirre‐Ghiso, Julio A.; Aplin, Andrew E.

doi:10.1158/1535-7163.mct-19-1016

Cited by 24 publications

(16 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Somatic copy-number alteration analyses from more than 3000 specimens have revealed that Ccnd1, Cdk4, Cdk6, and Ccne1 genes were listed in 30 of the most amplified genes associated with cancer, which highlight their potential as anti-cancer therapeutic targets [25,26]. Anti-cancer effects of the CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib in various types of cancers have been documented and these have all underwent phase III clinical trials [27][28][29][30]. Since the canonical pathway of CDK4/6/cyclin D-RB-E2F in the G1 phase is well-defined, we initially anticipated CDK4/6 inhibitor-induced G1 cell cycle arrest or quiescence in our study.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor-Induced CDKN2B and CDKN2D Contribute to G2/M Cell Cycle Arrest Incurred by Oxidative Stress in Hepatocellular Carcinoma Cells via Forkhead Box M1 Suppression

Lee¹,

Chu²,

Moon³

et al. 2021

J. Cancer

View full text Add to dashboard Cite

Forkhead box protein M1 (FOXM1) is a pivotal regulator of G2/M cell cycle progression in many types of cancer. Previously, our study demonstrated that histone deacetylase inhibition (HDACi) sensitizes hepatocellular carcinoma cells (HCC) to oxidative stress through FOXM1 suppression. However, the mechanism underlying its suppression by HDACi still requires elucidation. We hypothesized that HDACi induce genes responsible for destabilizing and inactivating FOXM1. The transcriptome in the HepG2 was revealed by massive analysis of cDNA end (MACE). Expression of mRNA and proteins were analyzed by quantitative real-time PCR (qPCR) and western blot, respectively. Cell cycle was analyzed by fluorescence-activated cell sorting (FACS). Oxidative stress and HDACi suppressed CDK4/6 levels while enhancing CDK inhibitor 2B and 2D (CDKN2B and CDKN2D) expressions in HCC. Palbociclib, a specific inhibitor of CDK4/6, induced G2/M cell cycle arrest in HCC by down-regulating phosphorylation level of FOXM1, and its downstream target genes such as aurora kinase A (AURKA) and polo-like kinase 1 (PLK1). HDACi treatment increased the ubiquitination level of FOXM1 by suppressing ubiquitin-specific peptidase 21 (USP21), which deubiquitinates FOXM1. Inhibiting FOXM1 degradation with MG132 treatment affected neither palbociclib-induced G2/M cell cycle arrest nor expression of its target genes. Double knockdown of CDKN2B and CDKN2D reduced the oxidative stress and HDACi-induced G/2M cell cycle arrest. In conclusion, oxidative stress and HDACi synergistically cause G2/M cell cycle arrest via CDKN2 induction, which sequentially inhibits CDK4/6, FOXM1, and its downstream target genes AURKA, PLK1, and CCNB1 phosphorylation in HCC.

show abstract

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor-Induced CDKN2B and CDKN2D Contribute to G2/M Cell Cycle Arrest Incurred by Oxidative Stress in Hepatocellular Carcinoma Cells via Forkhead Box M1 Suppression

Lee¹,

Chu²,

Moon³

et al. 2021

J. Cancer

View full text Add to dashboard Cite

show abstract

“…IACS-010759 is a clinical-grade small-molecule inhibitor of complex I of the electron transport chain [ 32 ]. IACS-010759 has been shown to selectively kill tumor cells that depend on OXPHOS, both in vitro and in preclinical models of human cancers with no cytotoxicity at tolerated doses in normal cells [ 32 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries

Zhang

Shetty

Clemente

et al. 2021

IJMS

View full text Add to dashboard Cite

Ovarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A, a member of the SWI/SNF chromatin-remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells; however, the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here, we show that ARID1A loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated with increase in c-Myc expression and increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 showed it extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide for the targeting mitochondrial activity in ARID1A-mutated OCCCs.

show abstract

“…Dynamic kinome reprogramming in response to CDK4i/6i has been reported in prostate adenocarcinoma (13), superficial spreading melanoma (14), and uveal melanoma (15) that results in therapy resistance via hyperactivation of the MAPK pathway. We next investigated the MAPK pathway following CDK4i/6i in our ALM system.…”

Section: Erk Hyperactivation Drives Intrinsic Cdk4i/6i Resistance Via...mentioning

confidence: 98%

ERK Hyperactivation Represents a Unified Mechanism of Escape in Intrinsic and Acquired CDK4/6 Inhibitor Resistance in Acral Lentiginous Melanoma

Jagirdar

Portuallo

Wilhide

et al. 2022

Preprint

View full text Add to dashboard Cite

Patients with metastatic acral lentiginous melanoma (ALM) suffer worse outcomes relative to patients with other forms of cutaneous melanoma (CM), and do not benefit as well to approved melanoma therapies. Identification of cyclin-dependent kinase 4 and 6 (CDK4/6) pathway gene alterations in >60% of ALMs has led to clinical trials of the CDK4/6 inhibitor (CDK4i/6i) palbociclib for ALM; however, median progression free survival with CDK4i/6i treatment was only 2.2 months, suggesting existence of resistance mechanisms. Therapy resistance in ALM remains poorly understood; here we report hyperactivation of MAPK signaling and elevated cyclin D1 expression are a unified mechanism of both intrinsic and acquired CDK4i/6i resistance. MEK or ERK inhibition increases CDK4i/6i efficacy in a patient-derived xenograft (PDX) models of ALM and promotes a defective DNA repair, cell cycle arrested and apoptotic program. Concurrent targeting of the MAPK pathway and CDK4/6 represents a new approach to improve outcomes for patients with advanced ALM.

show abstract

Metabolic Adaptations to MEK and CDK4/6 Cotargeting in Uveal Melanoma

Cited by 24 publications

References 48 publications

Histone Deacetylase Inhibitor-Induced CDKN2B and CDKN2D Contribute to G2/M Cell Cycle Arrest Incurred by Oxidative Stress in Hepatocellular Carcinoma Cells via Forkhead Box M1 Suppression

Histone Deacetylase Inhibitor-Induced CDKN2B and CDKN2D Contribute to G2/M Cell Cycle Arrest Incurred by Oxidative Stress in Hepatocellular Carcinoma Cells via Forkhead Box M1 Suppression

Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries

ERK Hyperactivation Represents a Unified Mechanism of Escape in Intrinsic and Acquired CDK4/6 Inhibitor Resistance in Acral Lentiginous Melanoma

Contact Info

Product

Resources

About