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Paradoxical activation of alternative pro‐survival pathways determines resistance to MEK inhibitors in chronic lymphocytic leukaemia
Author(s) -
Chen Yixiang,
Germano Sandra,
Shelmani Ghalia,
Kluczna Diana,
Jayne Sandrine,
Dyer Martin J. S.,
Macip Salvador
Publication year - 2018
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14880
Subject(s) - trametinib , mek inhibitor , mapk/erk pathway , selumetinib , cancer research , pi3k/akt/mtor pathway , medicine , protein kinase b , dabrafenib , kras , kinase , pharmacology , vemurafenib , melanoma , signal transduction , chemistry , cancer , biochemistry , colorectal cancer , metastatic melanoma
In order to explore novel therapeutic opportunities for B-cell malignancies, we evaluated the effects of MEK inhibitors (MEKi) on chronic lymphocytic leukaemia (CLL). We found that none had a significant effect on CLL viability, despite inhibiting signalling. Paradoxically, MEKi promoted the accumulation of active MEK and CRAF, reduced the expression of negative regulators of the pathway and augmented AKT signalling. Combining MEKi and phosphoinositide 3-kinase (PI3K) inhibitors antagonized this effect and induced cell death. We propose that MEKi-mediated activation of pro-survival pathways explains their low toxicity in CLL and that inhibition of both RAF/MEK/ERK and PI3K/ AKT signalling could overcome single-agent resistance. The RAF/MEK/ERK signalling cascade is activated in nearly half of CLL patients, suggesting a pathogenic role (Muzio et al, 2008). Selective inhibitors have been developed, including MEK1/2 inhibitors (MEKi) that are being clinically assessed as a monotherapy or in combination. However, MEKi have a lower efficiency in cancers not driven by mutant BRAF or KRAS, due to resistance mechanisms. This has limited the clinical use of these compounds. To test the effects of blocking the RAF/MEK/ERK pathway in CLL, we used different MEKi (U0126, PD0325901, selumetinib and trametinib) on the MEC-1 cell line, often used as a model for CLL, in which we observed increased RAF/MEK/ERK signalling (Chen et al, 2016). We used sorafenib (pan-RAF inhibitor) and dabrafenib (BRAF inhibitor) for comparison. Materials and methods are detailed in the Supplementary material. MEKi did not affect the viability (Fig 1A), survival (Figure S1A), cell cycle profile (Figure S1B), Mcl-1 levels or PARP cleavage (Figure S1C) in MEC-1, and only very high concentrations of sorafenib decreased Mcl-1 expression, cleaved PARP and induced death in MEC-1 (Fig 1A, S1A–C). Similar results were observed in JVM3, a