Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression

Hayes, Tikvah K.; Neel, Nicole F.; Hu, Chaoxin; Gautam, Prson; Chénard, Mélissa; Long, Brian J.; Aziz, Meraj; Kassner, Michelle; Bryant, Kirsten L.; Pierobon, Mariaelena; Marayati, Raoud; Kher, Swapnil S.; George, Samuel D.; Xu, Man; Wang‐Gillam, Andrea; Samatar, Ahmed A.; Maitra, Anirban; Wennerberg, Krister; Petricoin, Emanuel F.; Yin, Hongwei; Nelkin, Barry D.; Cox, Adrienne D.; Yeh, Jen Jen; Der, Channing J.

doi:10.1016/j.ccell.2015.11.011

Cited by 203 publications

(261 citation statements)

References 50 publications

(56 reference statements)

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“…The results were further confirmed in samples from our center, suggesting that MUC16 might be a mutant Kras target. Mounting evidence has pointed out c-Myc to be a Kras target (41). Moreover, we also reported that in pancreatic cancer, Kras mutation activated ERK, leading to destabilization of tumor suppressor FBW7, which ultimately led to c-Myc upregulation (24).…”

Section: Discussionmentioning

confidence: 82%

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

Liang

Qin

Zhang

et al. 2017

Molecular Cancer Research

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Section: Discussionmentioning

confidence: 82%

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

Liang

Qin

Zhang

et al. 2017

Molecular Cancer Research

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“…Approximately 30% of all cancers harbor RAS mutations; therefore, targeting downstream ERK1/2 with BVD-523 is a rational treatment approach for these cancers. Furthermore, results from a study by Hayes and colleagues indicate that prolonged ERK1/2 inhibition in KRAS-mutant pancreatic cancer is associated with senescent-like growth suppression (41). However, a combination approach may be required for maximal and durable attenuation of MAPK signaling in the setting of RAS mutations.…”

Section: Discussionmentioning

confidence: 99%

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

Germann

Furey

Markland

et al. 2017

Molecular Cancer Therapeutics

179

145

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Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a BRAF V600E -mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to singleagent and combination BRAF/MEK-targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway

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“…Melanoma Cells-We recently used a wholekinome siRNA screen to search for mechanisms of resistance to ERK inhibition in pancreatic ductal adenocarcinoma cell, and found that CK2␣ was one of the hits identified (22). To test whether CK2␣ promotes resistance to approved single agent therapies targeting the RAF-MEK-ERK pathway in melanoma cells with hyperactivation of this pathway, we first stably expressed FLAG-tagged wild-type CK2␣ in A375 melanoma cells ( Fig.…”

Section: Ck2␣ Promotes Resistance To Inhibitors Of Braf and Mek In Brmentioning

confidence: 99%

“…Considerable efforts have been invested in identifying resistance mechanisms of BRAF mutant melanomas to BRAF inhibition, and some have demonstrated clinical relevance (18 -21). In a recent whole-kinome siRNA screen for kinases that could induce resistance to ERK kinase inhibitors in pancreatic ductal adenocarcinoma cells, we identified CK2␣ as a synthetic lethal partner of ERK inhibition (22). We postulated that kinase inhibitor resistance mechanisms can be shared by diseases that show hyperactivity of the same pathway.…”

mentioning

confidence: 99%

Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma

Zhou¹,

Ritt

Morrison

et al. 2016

Journal of Biological Chemistry

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The protein kinase casein kinase 2 (CK2) is a pleiotropic and constitutively active kinase that plays crucial roles in cellular proliferation and survival. Overexpression of CK2, particularly the ␣ catalytic subunit (CK2␣, CSNK2A1), has been implicated in a wide variety of cancers and is associated with poorer survival and resistance to both conventional and targeted anticancer therapies. Here, we found that CK2␣ protein is elevated in melanoma cell lines compared with normal human melanocytes. We then tested the involvement of CK2␣ in drug resistance to Food and Drug Administrationapproved single agent targeted therapies for melanoma. In BRAF mutant melanoma cells, ectopic CK2␣ decreased sensitivity to vemurafenib (BRAF inhibitor), dabrafenib (BRAF inhibitor), and trametinib (MEK inhibitor) by a mechanism distinct from that of mutant NRAS. Conversely, knockdown of CK2␣ sensitized cells to inhibitor treatment. CK2␣-mediated RAF-MEK kinase inhibitor resistance was tightly linked to its maintenance of ERK phosphorylation. We found that CK2␣ post-translationally regulates the ERK-specific phosphatase dual specificity phosphatase 6 (DUSP6) in a kinase dependent-manner, decreasing its abundance. However, we unexpectedly showed, by using a kinase-inactive mutant of CK2␣, that RAF-MEK inhibitor resistance did not rely on CK2␣ kinase catalytic function, and both wild-type and kinase-inactive CK2␣ maintained ERK phosphorylation upon inhibition of BRAF or MEK. That both wild-type and kinase-inactive CK2␣ bound equally well to the RAF-MEK-ERK scaffold kinase suppressor of Ras 1 (KSR1) suggested that CK2␣ increases KSR facilitation of ERK phosphorylation. Accordingly, CK2␣ did not cause resistance to direct inhibition of ERK by the ERK1/2-selective inhibitor SCH772984. Our findings support a kinase-independent scaffolding function of CK2␣ that promotes resistance to RAF-and MEK-targeted therapies.The protein kinase casein kinase 2 or II (CK2) 2 is a highly conserved, ubiquitously expressed, pleiotropic, and constitutively active serine/threonine kinase that has crucial roles in cell survival, proliferation, and differentiation (2-4). The CK2 holoenzyme consists of two regulatory (␤) and two catalytic (␣ or ␣Ј) subunits, the latter of which can also function independently of the tetramer (5). Although CK2 itself does not appear to be a proto-oncogene, its up-regulation has been shown to promote growth and prevent apoptosis, both of which promote cancer (4). Indeed, overexpression of CK2 at the transcript and/or protein level has been observed in many cancers (6), including multiple myeloma (7), chronic lymphocytic leukemia (8), breast cancer (9), colorectal cancer (10), liver cancer (11), etc. and is correlated with poorer patient survival (6, 10, 12). Similarly, CK2 exhibited 2.5-fold higher catalytic activity in metastatic melanoma than in dermal nevi (13).In addition to its roles in tumor growth and progression, CK2 also promotes drug resistance to both conventional and targeted therapeutics. For example, pharmacological ...

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Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression

Cited by 203 publications

References 50 publications

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma

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