A recent study published in the journal PLos One found important genetic signalling pathways that may inhibit colorectal cancer (CRC) tumour proliferation.
The study entitled “Dual Pharmacological Targeting of the MAP Kinase and PI3K/mTOR Pathway in Preclinical Models of Colorectal Cancer”, was conducted by a team of researchers from the University of Colorado Cancer Center, and consisted of a Phase I clinical trial aimed at simultaneously targeting two cancer-causing pathways, the MAP Kinase and PI2K/mTOR pathway.
The rationale comes from evidence showing that two of the most implicated cellular pathways in cancers are the phosphatidylinositol-3 kinases (PI3K) and the mitogen activated protein kinase (MAPK) pathways.
The PI3K has been found to participate in a variety of signalling cancer pathways such as proliferation, differentiation, chemotaxis, survival, trafficking, and glucose homeostasis. Moreover, a mutation in PI3K has been found in 10–20% of CRC tumours. One of the components of the PI3K signalling pathway is the mammalian target of rapamycin (mTOR), which is implicated in cell growth, and a hyperactivation of the pathway PI3K/mTOR has been found to contribute to tumorigenesis, making it a target for inhibition.
Additionally, evidence shows that signalling the MAPK/ERK (MEK) pathway results in proliferation and resistance to apoptosis, whereas constitutive activation contributes to chemo resistance in several cancers. Mutations in KRAS, NRAS, or BRAF, which are MEK complexes, have been found in 50–60% CRC tumour samples.
In this study the researchers explored the efficacy of simultaneous inhibition of the PI3K/mTOR (PF-04691502/PF-502) in combination with the MEK (PD-0325901/PD-901) in mice models of the disease, using samples from human tumors (patient-derived CRC tumour xenograft models (PDTX)).
Results showed that after 30 days of exposure, the combination of a PI3K/mTOR and a MEK inhibitor was an effective anti-proliferation agent against CRC cell lines and PDTX models, which can have important implications for the development of combined treatment drugs.
In a recent press release , Dr. Todd Pitts, first author of the article, said “This study demonstrates strong potential for this combination in treating laboratory models of colorectal cancer. We hope that if we can discover biomarkers that predict which tumors respond and which don’t respond to the combination that we can optimize its use.”
The results from this study in conjunction with other ongoing clinical studies, indicate that patient selection for combination therapy in CRC is complicated and that other factors beyond mutation are implicated. The researchers suggest that novel technologies like next generation sequencing may lead to a more in-depth molecular characterization of cancer cells. Moreover, bioinformatics exploration can help to better-targeted combination therapies that can account for cancers with multiple drivers like colorectal cancer.