Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo

Abstract

Metastatic colorectal cancer (mCRC) is the second leading cause of cancer deaths in the United States. More than 50% of patients with mCRC harbor mutations of the oncogenic driver RAS (KRAS or NRAS). Because directly targeting most mutations of RAS is technically challenging, researchers have concentrated on targeting MEK, a downstream mediator of RAS. However, targeting MEK as single-agent therapy is ineffective in patients with mCRC. We hypothesize that combining a MEK inhibitor with other agents can enhance the efficacy of MEK targeting in mCRC. Unbiased high-throughput screening (HTS) was performed to identify drugs that enhance the efficacy of MEK inhibitors. HTS was performed with KRAS-mutated CRC cells using the MEK inhibitor trametinib as a “backbone” and two “clinically ready” compound libraries approved by the U.S. Food and Drug Administration or in clinical trials. HTS demonstrated that the combination of the SRC inhibitor dasatinib and trametinib was synergistic in CRC cells in vitro (MTT and colony formation assays). Analysis of markers for cell proliferation and apoptosis using fluorescence-activated cell sorting, reverse-phase protein array, or Western blotting demonstrated decreased cell proliferation and increased cell death when targeting both SRC and MEK as compared to single agents in multiple CRC cell lines. However, combining dasatinib and trametinib in vivo at doses in mice equivalent to doses used in humans failed to significantly enhance the antitumor activity of trametinib when compared to that of trametinib alone. These results underscore the importance of performing careful preclinical in vivo validation studies using clinically relevant doses as a prerequisite for translating in vitro findings to the clinic.

Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment

“…Further development combining MEK and MET inhibition [ 86 ] is being further evaluated in clinical studies (NCT02510001) to target both downstream signaling and putative adaptive resistance for the treatment of KRAS -mutant CRC. The challenges of targeting mutant KRAS and the insufficiency of MEK inhibition led to studies investigating complementary pathways to potentially enhance MEK inhibition resulting in the identification of Src inhibition with dasatinib as a potential effective combination treatment; but in vivo studies have not yet been successful with this approach [ 87 ].…”

Direct-Current Electrical Field Stimulation of Patient-Derived Colorectal Cancer Cells

“…Effects of signal transduction pathways associated with migration of CRC cells were addressed employing MK-2206, capivasertib, trametinib or niclosamide. The selected doses of MK-2206 [39,40], capivasertib [41], trametinib [42,43], and niclosamide [44,45] had previously shown antitumoral effects in various in vitro cancer models.…”