Tumor cells' drug addiction may be their downfall

May 02, 2019

Key points:

Blocking the processes that drive cancer cell growth is at the heart of many new anti-cancer therapies. Unfortunately, after initial success, cancer cells are generally able to develop workarounds to reactivate the pathways that promote growth. Work by researchers at the Babraham Institute in partnership with the global biopharmaceutical company AstraZeneca shows that this workaround strategy proves fatal for the cancer cells once the treatment compound is withdrawn. The research is published today in the journal Nature Communications.

One of the major cell signalling pathways controlling cell growth and division is the RAS-BRAF-MEK-ERK 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.

Dr Simon Cook and his team are specialists in the RAS-BRAF-MEK-ERK cell signalling pathway and through a long-standing partnership with collaborators at AstraZeneca had early access to a MEK inhibitor drug undergoing clinical testing to investigate how resistance to this drug develops.

"Tumours cells have shown themselves to be remarkably adaptable when treated with inhibitors of RAS-ERK signalling such as MEK or RAF inhibitors. Even in cases where these inhibitors are effective, invariably tumour cells adapt and acquire resistance to these drugs and their mechanisms of action," says Dr 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 signalling 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 signalling 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 defences.

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 tumour 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 anti-cancer 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 ageing 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," explains Dr 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," continues lead researcher Dr Mathew Sale, a member of Simon Cook's group. "Once the inhibitor drug is gone however, the mechanism devised to maintain ERK signalling 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 anti-cancer 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 tumour 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.
-end-


Babraham Institute

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.