Survival analysis of four independent CRC patient cohorts revealed that while the BRAF/MEK pathway was more strongly associated with recurrence than the ER pathway in mixed-stage CRCs, the ER pathway was a better predictor of recurrence than the BRAF/MEK pathway in stage II CRC.
Taken together, our findings suggest BOL is a novel therapeutic STAT3 inhibitor that can be used either alone or in combination with MEK inhibitors for the treatment of human CRC.
PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines.
By treating a panel of 47 human colorectal cancer cell lines with a combination of MEK- and PI3K-inhibitors, we observe a synergistic inhibition of growth in almost all cell lines.
Pfizer announced plans to acquire Array BioPharma, maker of a BRAF-MEK inhibitor combination that is currently approved for melanoma and could become a first-in-class treatment for colorectal cancer.
Together, these data establish CDK1 as a novel mediator of apoptosis resistance in <i>BRAF</i><sup>V600E</sup> colorectal cancers whose combined targeting with a MEK/ERK inhibitor represents an effective therapeutic strategy.<b>Implications:</b> CDK1 is a novel mediator of apoptosis resistance in <i>BRAF</i><sup>V600E</sup> colorectal cancers whose dual targeting with a MEK inhibitor may be therapeutically effective.<i></i>.
Using a recently described tumor-selective nanoparticle containing a β-catenin-targeting RNAi trigger, in combination with the FDA-approved MEK inhibitor (MEKi) trametinib, we demonstrate synergistic tumor growth inhibition in <i>in vivo</i> models of colorectal cancer, melanoma, and hepatocellular carcinoma.
Thus, targeting adaptive feedback pathways in <i>BRAF</i><sup>V600E</sup> colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.<b>Significance:</b> This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with <i>BRAF</i><sup>V600E</sup> colorectal cancer.
<i>BRAF</i><sup>V600E</sup> mutations occur in ∼10% of colorectal cancer cases, are associated with poor survival, and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition.
The combination of autophagy inhibition, anti-EGFR antibodies and checkpoint inhibitors as well as autophagy targeting, MEK inhibition and anti-EGFR antibodies or checkpoint inhibitors appears to be the best treatment approach for microsatellite instability high and stable colorectal cancer cell lines, respectively.
These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and colorectal cancers.
In summary, KRAS-mutant CRC shows intrinsic radioresistance along with rapid upregulation of hnRNP K in response to IR that can effectively be targeted by MEK inhibition.
Alterations in <i>MEK1/2</i> occur in cancers, both in the treatment-naïve state and following targeted therapies, most notably BRAF and MEK inhibitors in <i>BRAF</i>-V600E-mutant melanoma and colorectal cancer.
The response of BRAF mutant colorectal cancer to recent targeted strategies such as anti-BRAF or combinations with MEK and EGFR inhibitors remains limited and highly heterogeneous within BRAF V600E cohorts.
About 40% colorectal cancers (CRCs) contain KRAS or BRAF mutant genes and are resistant to treatments with individual inhibitors of RTKs, AKT, MEK, or BRAF.