The fight against cancer might be waged more successfully if it could borrow some ideas from the martial arts. Judo and jujitsu, for example, show how an attacker’s momentum can be redirected, unbalancing the attacker, even sending the attacker tumbling to the ground.
Cancer itself is capable of moves and countermoves. One of its favorite countermoves is acquired resistance to anticancer drugs. Although acquired resistance usually works to cancer’s advantage, it might also work to cancer’s disadvantage. According to researchers based at the Babraham Institute and AstraZeneca, at least one cancer inhibitor can be administered to upset cancer’s balance, such that some cancer cells lose resistance, while others become overcommitted to resistance, activating an aging pathway that leads to the arrest of cell growth.
Details of the scientists’ work appeared May 2 in the journal Nature Communications, in an article titled, “MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance.” As the title suggests, some cancer moves may be easier to exploit than others.
The new work benefits for research into the RAS-BRAF-MEK-ERK cell signaling pathway. Consisting of three enzymes working in a linear cascade, the pathway leads to the activation of ERK to promote cell division. Many cancers, including most melanomas and some colon cancers, arise due to mutations in the BRAF kinase, which results in an unprompted growth signal and inappropriate cell division.
At the Babraham Institute, Simon Cook, group leader, and his team are specialists in the RAS-BRAF-MEK-ERK cell signaling pathway. Through a long-standing partnership with collaborators at AstraZeneca, Cook and colleagues had early access to a MEK inhibitor drug undergoing clinical testing to investigate how resistance to this drug develops.
“Tumor cells have shown themselves to be remarkably adaptable when treated with inhibitors of RAS-ERK signaling such as MEK or RAF inhibitors. Even in cases where these inhibitors are effective, invariably tumor cells adapt and acquire resistance to these drugs and their mechanisms of action,” said Paul Smith, lead researcher at AstraZeneca. “Working with Simon Cook and his team at the Babraham Institute allowed us to apply their expert knowledge in cell signaling to better understand the mechanism of acquired resistance and excitingly, it has led to results that might change how MEK and other RAS-ERK pathway inhibitors, could be used for the treatment of cancer.”
Simon Cook and his team used an AstraZeneca-developed MEK inhibitor called selumetinib (AZD6244/ARRY-142886) to study how resistance arises. After exposure of human cancer cell lines to selumetinib over several weeks, resistant cells arose through a process called gene amplification where the cells multiply their copies of their addicted oncogene, the mutated BRAF gene. This amplification of BRAF maintains growth signaling through ERK by overwhelming the presence of the drug working to shut down this pathway in much the same way as a tidal surge can overwhelm flood defenses.
The researchers found that if they stopped treating the selumetinib resistant cells with the drug, their resistance to it was rapidly lost so that the tumor cells reverted back to being fully drug sensitive (by 5–10 weeks of growth in the absence of selumetinib depending on cell type).
The researchers were intrigued to find out why as this might tell us something important about how cell growth is controlled and might have relevance to the way new anticancer drugs are administered to patients.
They found that BRAF gene amplification becomes an impediment for cells in a drug-free environment because the cells are locked into abnormally high ERK activation. As a result of high ERK activity, a cellular aging pathway is activated and the cells enter a permanent arrest of cell growth. Cells showing only modest levels of BRAF and ERK activity survive in this pool of cells and can divide but reacquire drug sensitivity so can be eliminated by a second wave of the drug.
“We know that cells need to maintain a level of activated ERK within a very specific range,” explained Cook. “Rather than promoting more growth, too much ERK actually halts cell growth.”
“In the presence of the inhibitor drug, the resistance mechanism sustains the cell’s ERK level and cell growth,” continued lead researcher Mathew Sale, a member of Simon Cook’s group. “Once the inhibitor drug is gone, however, the mechanism devised to maintain ERK signaling actually pushes the levels into the ‘too high’ zone—where the cell can no longer divide and often enters a phase of sustained growth inhibition and sometimes death.”
In cell culture at least, this is a mechanism whereby the withdrawal of the anticancer drug can be used to eliminate resistant cells, clearing them from the population.
A previous study in laboratory mice has shown that intermittent dosing of similar drugs may elicit a more prolonged inhibition of tumor growth but the mechanism underlying this effect was not clear. This new study clearly defines the ERK “sweet spot” as the determinant of reversibility, suggesting that in the case of cancers involving BRAF mutations, future clinical trials should consider intermittent dosing regimens to forestall the development of drug resistance.