MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road

Caunt, Christopher J.; Sale, Matthew J.; Smith, Paul D.; Cook, Simon J.

doi:10.1038/nrc4000

Cited by 509 publications

(544 citation statements)

References 197 publications

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“…S15). Moreover, suppression of MAPK signaling with the U0126 and the PD0325901 MEK inhibitors (33) showed increased antileukemic activity in Kras G12D mutant cells and enhanced the cytotoxic activity of methotrexate (Fig. 3 F and G and SI Appendix, Figs.…”

Section: Resultsmentioning

confidence: 99%

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

Oshima

Khiabanian

Silva-Almeida

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

115

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Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK pathway-activating mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), kirsten rat sarcoma viral oncogene homolog (KRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) genes were present in 24 of 55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, whereas in others RAS mutant clones present at diagnosis were replaced by RAS wildtype populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Consistently, functional dissection of mouse and human wild-type and mutant RAS isogenic leukemia cells demonstrated induction of methotrexate resistance but also improved the response to vincristine in mutant RAS-expressing lymphoblasts. These results highlight the central role of chemotherapy-driven selection as a central mechanism of leukemia clonal evolution in relapsed ALL, and demonstrate a previously unrecognized dual role of RAS mutations as drivers of both sensitivity and resistance to chemotherapy.acute lymphoblastic leukemia | relapsed leukemia | chemotherapy resistance | genome sequencing A cute lymphoblastic leukemia (ALL) is the most common malignancy in children (1-4). Current therapy of pediatric newly diagnosed ALL includes initial clearance of leukemic lymphoblasts with cytotoxic drugs and glucocorticoids followed by delivery of chemotherapy to the central nervous system and a prolonged lower intensity maintenance treatment phase aimed at securing long-term remission by reducing the rates of leukemia relapse (3). Altogether 95% of pediatric ALL patients achieve a complete hematologic remission during induction and 80% of them remain leukemia free (5). However, the prognosis of patients showing refractory disease or those whose leukemia relapses after an initial transient response remains disappointingly poor, with cure rates of less than 40% (6, 7). Several mechanisms have been implicated as drivers of leukemia relapse, including the presence of rare quiescent and intrinsically chemoresistant leukemia stem cells with increased self-renewal capacity (8), protection from chemotherapy by safe-haven microenvironment niches (9, 10), and selection of secondary genetic alterations promoting chemotherapy resistance in leukemic lymphoblasts (11)(12)(13). In this regard, early studies described the presence of tumor protein p53 (TP53) mutations in relapsed ALL, supporting a role for escape from genotoxic stress in leukemia progression (14). Similarly, lo...

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Section: Resultsmentioning

confidence: 99%

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

Oshima

Khiabanian

Silva-Almeida

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

115

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“…The deregulation of MAPK pathway represents some of the driving characteristics and key hallmarks of the cancer cell (Hanahan and Weinberg, 2000, 2011). Consequently, many cancers bearing these MAPK‐related mutant genes exhibit a survival addiction to ERK1/2 signaling (Caunt et al ., 2015; Kidger and Keyse, 2016). RAF and MEK inhibitors therefore are being developed as treatments for cancers with activated RAF/MEK/ERK signaling.…”

Section: Introductionmentioning

confidence: 99%

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

et al. 2017

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Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2‐positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase‐dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin‐dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK‐mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor‐induced Akt activation.

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“…numerous cellular and developmental processes. 18,19 The somatic mutations we identified cluster within or adjacent to the protein's negative regulatory domain ( Figure 2); they have been observed in neoplasms, including melanoma, lung cancer, and hematopoietic malignancies, [20][21][22][23][24][25] and have been shown to constitutively increase MEK1 activity. [26][27][28] MEK1 and its paralog MEK2 phosphorylate ERK1 and ERK2.…”

mentioning

confidence: 99%

“…MEK1 inhibitors currently are in use against various cancers. 18 Further study is required to determine whether these drugs have efficacy for AVM. Current agents are cytostatic rather than cytotoxic, but might benefit individuals with AVM if they cause mutant When no MAP2K1 mutation was detected in affected tissue, the denominator for the ddPCR assay is the sum of wild-type droplets for the four individual assays.…”

mentioning

confidence: 99%

Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation

Couto

Huang

Konczyk

et al. 2017

The American Journal of Human Genetics

235

171

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Arteriovenous malformation (AVM) is a fast-flow, congenital vascular anomaly that may arise anywhere in the body. AVMs typically progress, causing destruction of surrounding tissue and, sometimes, cardiac overload. AVMs are difficult to control; they often re-expand after embolization or resection, and pharmacologic therapy is unavailable. We studied extracranial AVMs in order to identify their biological basis. We performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) on AVM tissue from affected individuals. Endothelial cells were separated from non-endothelial cells by immune-affinity purification. We used droplet digital PCR (ddPCR) to confirm mutations found by WES and WGS, to determine whether mutant alleles were enriched in endothelial or non-endothelial cells, and to screen additional AVM specimens. In seven of ten specimens, WES and WGS detected and ddPCR confirmed somatic mutations in mitogen activated protein kinase kinase 1 (MAP2K1), the gene that encodes MAP-extracellular signal-regulated kinase 1 (MEK1). Mutant alleles were enriched in endothelial cells and were not present in blood or saliva. 9 of 15 additional AVM specimens contained mutant MAP2K1 alleles. Mutations were missense or small in-frame deletions that affect amino acid residues within or adjacent to the protein's negative regulatory domain. Several of these mutations have been found in cancers and shown to increase MEK1 activity. In summary, somatic mutations in MAP2K1 are a common cause of extracranial AVM. The likely mechanism is endothelial cell dysfunction due to increased MEK1 activity. MEK1 inhibitors, which are approved to treat several forms of cancer, are potential therapeutic agents for individuals with extracranial AVM.Arteriovenous malformation (AVM) is a congenital vascular anomaly, comprised of abnormal connections between arteries and veins that are missing normal high-resistance capillary beds (Figure 1). 1 Sporadic extracranial AVMs are solitary and may be localized or regional. Rapid blood flow is demonstrable by Doppler ultrasonography. Magnetic resonance imaging reveals signal voids consistent with fast-flow, while angiography shows the early filling of draining veins (Figure 1). With time, arterial to venous shunting causes tissue ischemia that leads to pain, ulceration, bleeding, and destruction of adjacent tissues. Treatment for AVM has been discouraging. Embolization and/or resection are often followed by expansion; there are no drug treatments. 2 The purpose of this study was to identify the genetic basis for sporadic, extracranial AVM in an effort to devise a new therapeutic strategy.The Committee on Clinical Investigation at Boston Children's Hospital approved this study and informed consent was obtained from study participants. Ten AVM specimens that had been collected during a clinically indicated procedure, including matched unaffected tissue specimens from three of the study participants, had DNA extracted using the DNeasy Blood & Tissue Kit (QIAGEN); saliva DNA was extracted using the pr...

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MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road

Cited by 509 publications

References 197 publications

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation

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