2.
Co-inhibition of MEK and mutual feedback/crosstalk networks for reversing MEKi resistance and improving therapeutic efficacy
| Strategy | Combination | Antitumor efficacy | Tumor model | Ref |
| ACT, adoptive cell transfer. | ||||
| MEK+BRAF | Binimetinib+
encorafenib |
Binimetinib: moderate TGI
Encorafenib: minimal TGI Combination: >80% of TGI, 10-fold enhancement in apoptosis, 7-12 fold increase in the expression of pro-apoptotic proteins |
NRAS or BRAF-mutant melanoma models: monolayer, spheroids, organotypic, and patient-derived tissue slice | 97 |
| MEK+BRAF | Cobimetinib+
vemurafenib |
mPFS: 9.9 months/combination, 6.2 months/control
ORR: 68%/combination, 45%/control CRR: 10%/combination, 4%/control 9-month survival rate: 81%/combination, 73%/control Decreased the morbidity of secondary cutaneous cancers. No apparent AEs of grade 3 or higher |
Advanced or metastatic BRAF V600-mutant melanoma | 98 |
| MEK+BRAF+
HER2 |
Selumetinib+
dabrafenib+ lapatinib |
Lapatinib markedly sensitized cancer cells to dose-dependent inhibition, improved the iodine and glucose-handling gene expression, radioiodine uptake, and prevented the MAPK rebound induced by the BRAF/MEK inhibitor | BRAF V600E-mutant papillary thyroid cancer | 21 |
| MEK+BRAF+
HER2 |
U0126/
selumitinib+ sorafenib+ lapatinib |
The combination induced distinguishable tumor inhibition, greater MAPK suppression and curative activity than alone | TNBC models | 99 |
| MEK+EGFR | Selumetinib/
cetuximab+ osimertinib |
RR: 80%/combination,
50%/alone mPFS: 28 weeks Inhibited proliferation, migration, and invasion of resistant cells |
EGFR-mutant NSCLC xenografts | 100 |
| MEK+BRAF+
immunotherapy |
BRAF/MEK
inhibitor+PD-1 inhibitor |
Two drugs are positively correlated at low doses,
while antagonistic at some high doses |
Animals, early and advanced clinical trials | 101 |
| MEK+BRAF+
immunotherapy |
Trametinib+
dabrafenib+ antigen- specific ACT |
The triple combination showed complete tumor regression, increased T cell infiltration into tumors, improved in vivo cytotoxicity, increased MHC expression, and global immune gene up-regulation | BRAF V600E-mutant melanoma | 102 |
| MEK+ERK | PD0325901/
G-573+ERK inhibitor |
MEK resistant KRAS mutant cells retain sensitivity to ERK inhibition.
Downstream blockade of ERK overcome multiple resistance mechanisms of MEKi |
KRAS mutant breast cancer and CRC | 87 |
| MEK+ERK | GSK1120212+
SCH772984 |
The combination showed significant tumor regression potency (98% regression), and relieved the resistance to MEKi, BRAFi, and MEK/BRAF inhibitors | RAS or BRAF-mutant CRC, melanoma, and pancreatic cancer | 18 |
| MEK+ERK | Cobimetinib+
GDC-0994 |
In PDAC model, combination reduced tumor volume in 5/8 of animals, repressed p90RSK, and improved PFS (18.5 vs. 7 days in vehicle).
In NSCLC model, combination resulted in overall tumor burden decrease (10/10), strong suppression of p90RSK, and improved PFS (102 vs. 58 days in vehicle) |
KRAS or BRAF-mutant NSCLC, melanoma, and PDAC | 104 |
| MEK+CDK1 | Cobimetinib+
R0-3306/ dinaciclib |
The combination greatly inhibited cell proliferation, suppressed tumor growth, and promoted apoptosis by cleavage of PARP and caspase-3 | BRAF-mutant CRC murine xenografts | 105 |
| MEK+PI3K+
mTOR |
Selumetinib+
ZSTK474+ BEZ235 |
The combination synergistically inhibited the phosphorylation of ERK, AKT, S6 and the tumor growth, with statistically significant TGI of (21.8±6.6)%, (19.9±8.3)%, (37.9±6.9)%, (75.8±3.1)%, and (59.0±7.4)% corresponding to ZSTK474, BEZ235, selumetinib, BEZ235+selumetinib, and ZSTK474+selumetinib at day 14 after administration | BRAF-mutant metastatic melanoma | 110 |
| MEK+PI3K+
PDGFR |
Selumetinib+
buparlisib+ pazopanib |
The combination decreased MAPK and PI3K signaling, changed the kinome in MAPK pathway, altered the resistance drivers, and managed TNBC brain metastasis | TNBC brain metastases model | 112 |
| MEK+PI3K+
HDAC |
GSK1120212+
BEZ235+TSA |
The combination inhibited cell proliferation by >99%, no observable lung metastatic foci, compared with the average of 8.1±1.7 foci per mouse in BEZ/GSK combination and 10±2 foci in vehicle | Highly aggressive and metastatic PDAC mouse model | 113 |
| MEK+AKT | CH5126766/
trametinib+ statins |
The combination enhanced the cell sensitivity, reversed the apoptotic resistance to MEKi by up-regulating the TRAIL, and improved the antitumor efficacy of MEKi | Human breast cancer MDA-MB-231 apoptotic resistant model | 115 |
| MEK+AKT+
mTOR |
AZD6244+
MK-2206+ AZD8055 |
The combination synergistically enhanced the effect of MEKi on cell proliferation and survival with combination index below 0.3 | Advanced CCA model | 116 |
| MEK+HSP90 | Trametinib+
AUY922 |
The combination suppressed MAPK and AKT pathways, sensitized NSCLC cells to MEKi, and increased apoptosis through cleaved PARP and caspase-3/7 pathway with sub-therapeutic doses | NSCLC model | 117 |
| MEK+Wnt | Selumetinib+
CsA/TNP-470 |
The combination recovered the cell responsiveness to selumetinib, showed synergistic anti-proliferative effect in CRC cells, effectively regressed tumor growth and promoted apoptosis of the PDTX models of CRC | Clinically relevant PDTX models of CRC | 118 |
| MEK+
β-catenin |
Trametinib+
RNAi trigger of β-catenin |
The combination synergistically inhibited tumor growth with >90% of TGI vs. 60% of single dosage, overcame the resistance to trametinib, and improved the mice survival in all selected tumor models | Xenografts of CRC, melanoma, and HCC | 119 |
| MEK+
HGF/cMET |
Trametinib+
LY2875358+ LY2801653 |
The combination reversed the resistance to trametinib, suppressed AKT activation, and promoted the pro-apoptotic PARP cleavage | Primary hepatic stellate cells, metastatic uveal melanoma explants | 120 |
| MEK+RIP1 | Selumetinib+
Nec-1 |
The combination overcame the resistance to selumetinib caused by the CYLD-relied activation of NF-κB pathway, and enhanced efficacy in cancer treatment | Melanoma cells | 121 |