Abstract
Genomic alterations in cancer cells result in vulnerabilities that clinicians can exploit using molecularly targeted drugs, guided by knowledge of the tumour genotype. However, the selective activity of these drugs exerts an evolutionary pressure on cancers that can result in the outgrowth of resistant clones. Use of rational drug combinations can overcome resistance to targeted drugs, but resistance may eventually develop to combinatorial therapies. We selected MAPK- and PI3K-pathway inhibition in colorectal cancer as a model system to dissect out mechanisms of resistance. We focused on these signalling pathways because they are frequently activated in colorectal tumours, have well-characterised mutations and are clinically relevant. 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. Cells with KRAS mutations are less sensitive to PI3K inhibition, but are particularly sensitive to the combined treatment. Colorectal cancer cell lines with inherent or acquired resistance to monotherapy do not show a synergistic response to the combination treatment. Cells that acquire resistance to an MEK–PI3K inhibitor combination treatment still respond to an ERK–PI3K inhibitor regimen, but subsequently also acquire resistance to this combination treatment. Importantly, the mechanisms of resistance to MEK and PI3K inhibitors observed, MEK1/2 mutation or loss of PTEN, are similar to those detected in the clinic. ERK inhibitors may have clinical utility in overcoming resistance to MEK inhibitor regimes; however, we find a recurrent active site mutation of ERK2 that drives resistance to ERK inhibitors in mono- or combined regimens, suggesting that resistance will remain a hurdle. Importantly, we find that the addition of low concentrations of the BCL2-family inhibitor navitoclax to the MEK–PI3K inhibitor regimen improves the synergistic interaction and blocks the acquisition of resistance.
Highlights
Over recent years an improved understanding of the molecular basis of cancer has led to the concept of precision medicine, where treatment with targeted drugs is guided by knowledge of the patient’s tumour genotype [1]
Combination treatment regimens have several advantages over monotherapy: they may increase antitumour effects within acceptable toxicity limits, are more likely to be effective against a heterogeneous tumour population and may delay or block the development of drug resistance [39]
Initial sensitivity profiling work was followed up with a focused strategy using a single colorectal cancer cell line model to identify mechanisms of resistance. While the latter approach may not define the full spectrum of resistance in colorectal cancer, we did find resistance mechanisms, namely loss of PTEN and mutation of MEK1/2, that were previously reported in clinical resistance to MEK and phosphatidylinositol 3-kinase (PI3K) inhibitors [26, 40], validating the approach
Summary
Over recent years an improved understanding of the molecular basis of cancer has led to the concept of precision medicine, where treatment with targeted drugs is guided by knowledge of the patient’s tumour genotype [1]. This approach can be successful, the selective pressure that targeted agents exert can result in the outgrowth of resistant. A significant proportion of colorectal tumours have genetic abnormalities that activate Both pathways [14], resulting in a reduced response to monotherapy. We find that prolonged exposure to a PI3K inhibitor plus an MEK- or ERK-inhibitor leads to the emergence of resistance; importantly, this resistance can be overcome by cotreatment with a BCL2-family inhibitor
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