Mutations in KRAS are found in more than 50% of
tumors from patients with metastatic
colorectal cancer (mCRC). However, direct targeting of most KRAS mutations is difficult; even the recently developed KRASG12C inhibitors failed to show significant benefit in patients with mCRC. Single agents targeting
mitogen-activated protein kinase kinase (
MEK), a downstream mediator of RAS, have also been ineffective in
colorectal cancer. To identify drugs that can enhance the efficacy of
MEK inhibitors, we performed unbiased high-throughput screening using
colorectal cancer spheroids. We used
trametinib as the anchor
drug and examined combinations of
trametinib with the NCI-approved Oncology Library version 5. The initial screen, and following focused validation screens, identified
vincristine as being strongly synergistic with
trametinib. In vitro, the combination strongly inhibited cell growth, reduced clonogenic survival, and enhanced apoptosis compared with monotherapies in multiple KRAS-mutant
colorectal cancer cell lines. Furthermore, this combination significantly inhibited
tumor growth, reduced cell proliferation, and increased apoptosis in multiple KRAS-mutant patient-derived xenograft mouse models. In vivo studies using
drug doses that reflect clinically achievable doses demonstrated that the combination was well tolerated by mice. We further determined that the mechanism underlying the synergistic effect of the combination was due to enhanced intracellular accumulation of
vincristine associated with
MEK inhibition. The combination also significantly decreased p-mTOR levels in vitro, indicating that it inhibits both RAS-RAF-
MEK and PI3K-AKT-mTOR survival pathways. Our data thus provide strong evidence that the combination of
trametinib and
vincristine represents a novel therapeutic option to be studied in clinical trials for patients with KRAS-mutant mCRC.
SIGNIFICANCE: