Therapeutic potential of MEK inhibition in acute myelogenous leukemia: rationale for “vertical” and “lateral” combination strategies

Ricciardi, Maria Rosaria; Scerpa, Maria Cristina; Bergamo, Paola; Ciuffreda, Ludovica; Petrucci, Maria Teresa; Chiaretti, Sabina; Tavolaro, Simona; Mascolo, Maria Grazia; Abrams, Stephen L.; Steelman, Linda S.; Tsao, Twee; Marchetti, Antonio; Konopleva, Marina; Bufalo, Donatella Del; Cognetti, Francesco; Foà, Robin; Andreeff, Michael; McCubrey, James A.; Tafuri, Agostino; Milella, Michèle

doi:10.1007/s00109-012-0886-z

Cited by 38 publications

(36 citation statements)

References 33 publications

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“…It has been postulated that higher baseline level of p-ERK predicts sensitivity to MEK inhibition in AML cell lines and primary AML samples. (25) Therefore, we analyzed p-ERK at baseline, and confirmed p-ERK activation in the majority of patients (85%) evaluated at baseline, but there was no correlation with treatment outcome. Larger studies are needed to confirm this finding, although our experience is similar to that of Bekaii-Saab and colleagues, who also reported no correlation between p-ERK activation and clinical outcomes in patients with metastatic biliary cancer treated with selumetinib.…”

Section: Discussionmentioning

confidence: 87%

“…Although dysregulation of the RAS/RAF/MEK/ERK pathway has been shown to be important in leukemogenesis, and pharmacologic inhibition of MEK has also been shown to inhibit the growth of leukemic cell lines and primary AML samples in vitro,(10, 24, 25) this is the first study to attempt to document, in vivo , the potential clinical relevance of targeting this pathway in relapsed/refractory AML.…”

Section: Discussionmentioning

confidence: 98%

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Phase II Study of the Oral MEK Inhibitor Selumetinib in Advanced Acute Myelogenous Leukemia: A University of Chicago Phase II Consortium Trial

Jain

Curran

Iyengar

et al. 2014

Clinical Cancer Research

105

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Purpose The clinical relevance of targeting RAS/RAF/MEK/ERK pathway, activated in 70-80% of acute myeloid leukemia (AML) patients, is unknown. Experimental Design Selumetinib is an oral small molecule inhibitor of MEK1/2 kinase. Forty-seven patients with relapsed/refractory AML or ≥60 years old with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial and minor). Leukemia cells were analyzed for ERK and mTOR phosphorylation. Results Common drug-related toxicities were grade I-II diarrhea, fatigue, nausea, vomiting and skin rash. In the FLT3 wild type cohort, 6/36 (17%) patients had a response [1 partial response, 3 minor responses, 2 unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single nucleotide polymorphism (SNP) rs3733542 in exon 18 of KIT gene was detected in significantly higher number of patients with response/stable disease compared with non-responders (60% vs 23%; p=0.027). Conclusion Selumetinib is associated with modest single agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 98%

Phase II Study of the Oral MEK Inhibitor Selumetinib in Advanced Acute Myelogenous Leukemia: A University of Chicago Phase II Consortium Trial

Jain

Curran

Iyengar

et al. 2014

Clinical Cancer Research

105

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“…Some scientists and clinicians have considered that the simultaneous targeting of Raf and MEK by individual inhibitors may be more effective in cancer therapy than just targeting Raf or MEK by themselves (Ricciardi et al 2012). This is based in part on the fact that there are intricate feed-back loops from ERK which can inhibit Raf and MEK.…”

Section: Discussionmentioning

confidence: 99%

“…Little is known about the differential in vivo targets of ERK1 and ERK2. The development of specific ERK1 and ERK2 inhibitors is ongoing and may be useful in the treatment of certain diseases such as those leukemias where elevated ERK activation is associated with a poor prognosis (e.g., AML, ALL) (Ricciardi et al 2012). ERK inhibitors have been described (Aronov et al 2009).…”

Section: Erk Inhibitorsmentioning

confidence: 97%

Raf/MEK/ERK Signaling

McCubrey

Steelman

Bäsecke

et al. 2014

Targeted Therapy of Acute Myeloid Leukemia

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The Ras/Raf/MEK/ERK cascade is often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, and MEK1 are also deregulated by mutations. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. This pathway has profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of this pathway can contribute to: resistance to other pathway inhibitors and chemotherapeutic drugs. Intense scientific, commercial, and clinical interest has developed over the past decade in elucidating the functions of this pathway in leukemia and other blood cancers. Targeting this pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type RAF in the presence of mutant, activated RAS). Furthermore, targeting with inhibitors directed at two constituents of the same pathway may be a more effective approach. This chapter will first describe these pathways and then evaluate potential uses of Raf and MEK inhibitors that have been investigated in pre-clinical and clinical investigations.

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“…In acute myelogenous leukemia cell lines and clinical samples, a growth inhibitory and pro-apototic effect of the MEK inhibitor PD0325901, in parallel with ERK phosphorylation inhibition, has been reported [89]. In this context, compensatory up-regulation of components of the Raf/MEK/ERK pathway or of other survival pathways (e.g., mTOR) suggested the use of rationally defined combinations [92].…”

Section: Inhibition Of the Erk Pathway As A Drug Sensitizing Approachmentioning

confidence: 98%

Modulation of Sensitivity to Antitumor Agents by Targeting the MAPK Survival Pathway

Cossa¹,

Gatti²,

Cassinelli³

et al. 2013

Current Pharmaceutical Design

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Mitogen-activated protein kinases (MAPK) are involved in a complex network which regulates a variety of cellular processes including proliferation, survival and death. The molecular characterization of the pathway has shown aberrant activation in several human tumors, due to the deregulation of receptor tyrosine kinases or to mutations of pathway components. Progress in understanding the MAPK network has led to the development of target-specific agents in clinical trials. The relevance of MAPK in response and resistance to antitumor agents has been recognized, although the outcome of MAPK activation can vary depending on the molecular background of tumor cells and on the type of activated kinase. The canonical cascade of MAPK, i.e., depending on the Extracellular Signal-Regulated Kinases (ERK), can act in protective signalling pathways, thereby limiting DNA damage. Since tumor cell survival can be sustained by ERK and cross talk of ERK with other pathways, modulation of sensitivity to antitumor agents by targeting the ERK cascade appears to be an amenable approach. Indeed, ERK play a role in resistance to both cytotoxic and target-specific agents. Preclinical studies support the relevance of drug combination approaches to enhance the efficacy of antitumor treatments. Combinations of pharmacological inhibitors of the ERK cascade and conventional or target-specific antitumor agents may be helpful in an attempt to overcome drug resistance. A deeper understanding of the genetic alterations of tumor cells and of tumor heterogeneity as well as of drug resistance mechanisms is expected to contribute to the rational design of MAPK-mediated drug combinations that will lead to reversal of drug resistance.

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Therapeutic potential of MEK inhibition in acute myelogenous leukemia: rationale for “vertical” and “lateral” combination strategies

Cited by 38 publications

References 33 publications

Phase II Study of the Oral MEK Inhibitor Selumetinib in Advanced Acute Myelogenous Leukemia: A University of Chicago Phase II Consortium Trial

Phase II Study of the Oral MEK Inhibitor Selumetinib in Advanced Acute Myelogenous Leukemia: A University of Chicago Phase II Consortium Trial

Raf/MEK/ERK Signaling

Modulation of Sensitivity to Antitumor Agents by Targeting the MAPK Survival Pathway

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