News ID: 255659
Published: 0927 GMT July 12, 2019

Combination of breast, lung cancer drugs could overcome tumor resistance

Combination of breast, lung cancer drugs could overcome tumor resistance
jerseyeveningpost.com

Two drugs that are used for breast and lung cancer could be combined to overcome tumor resistance in several types of the disease, new research suggests.

A study found that breast-cancer medication palbociclib was boosted when combined with the lung-cancer treatment crizotinib, dailymail.co.uk wrote.

When tested on both cancer cells in the laboratory and mice with a range of malignant tumors, the duo was significantly more effective than the individual drugs.

The combined treatment both blocked cell division and induced senescence, which occurs when a cell loses its 'power' to divide and grow.

While palbociclib has been described as one of the biggest treatment advances for advanced breast cancer in the past two decades, some tumors develop resistance to it.

This is often driven by a protein that crizotinib targets, with the two drugs together helping to overcome cancer cell resistance.  

The research was carried out by The Institute of Cancer Research (ICR) in London and University College London's (UCL) Cancer Institute.

It was co-led by Professor Paul Workman, chief executive of the ICR and Dr. Sibylle Mittnacht, professor of molecular cancer biology at UCL.

Mittnacht said: “Our evidence shows that existing medicines could be used to overcome resistance to treatment in a frequent form of breast cancer in women.

“In addition, use of a current breast cancer medicine together with these other medicines could be a new, promising route for the treatment of lung and several other cancers.'

Workman added: “Cancer's ability to adapt, evolve and become drug resistant is the biggest challenge we face in creating more effective treatments for the disease.

“We have shown the potential of combining two precision medicines for breast and lung cancer together to create a two-pronged attack that strips cancer cells of their resistance.”

Breast cancer affects one in eight women at some point in their lives in the UK and US, statistics show.

When it comes to lung cancer, 47,235 cases were diagnosed between 2014 and 2016 in the UK, Cancer Research UK statistics show.

And in the US, around 234,000 people were told they had lung cancer last year, according to the American Lung Association.

Palbociclib is used to treat hormone receptor-positive breast cancer. These tumors come about as a direct result of the many hormone receptors on the surface of breast cells.

In the case of estrogen receptor-positive breast cancer, the cancerous cells receive growth signals from the hormone.

Palbociclib blocks two proteins called CDK4 and CDK6, which promote tumor cell division and cancer progression.

Tumors can become resistant to palbociclib by activating a molecule called CDK2, which drives cell division even if CDK4 and CDK6 are inactive.

CDK2 is thought to do this via a signaling pathway that involves the molecules MET and FAK. 

Crizotinib has been shown to block MET.

The researchers therefore speculated whether combining the two drugs could overcome CDK2's tumor-fueling mechanism.

The treatment combination was tested in both cancer cells that were grown in the laboratory and human tumors that were transplanted into mice. 

These cancer types included everything from breast and lung to bowel.

Results — published in the journal Oncogene —    revealed the duo therapy worked together to both stop the cancer cells dividing and induce senescence.

The combined treatment's effectiveness across a range of cancer types suggests palbociclib has potential beyond just breast forms of the disease. 

In a second part of the experiment, the researchers set out to uncover how palbociclib resistance comes about.

Robotics and sophisticated imaging were used to identify how CDK2 is activated to allow rapidly-dividing cells to avoid CDK4 and CDK6 inhibitors.

The researchers discovered MET and FAK are critical molecules in the signaling pathway used by tumors to survive and develop palbociclib resistance.

Before the combined treatment can be used in patients, the safety and effectiveness of combining CDK4 and CDK6 inhibitors like palbociclib with MET inhibitors like crizotinib must be studied, the researchers said.

If these studies are successful, it may be possible to develop laboratory tests that identify which patients would benefit from using crizotinib in this way, they added.

And looking further into the future, CDK4 and CDK6 inhibitors could be combined with drugs that block FAK.

FAK was shown to be critical in the activation of unwanted CDK2. Inhibitors against this molecule are already being tested in clinical trials.

“We still need to do more work to understand the full potential of combination treatment to increase the effectiveness of these drugs,' Workman said.

“But the approach looks highly promising and has the potential to be effective against several cancer types.'

Combining different drugs with varying modes of action is a central strategy of the ICR's research program to combat cancers' ability to adapt, evolve and become drug resistant.

The ICR is raising the final £15million ($18.6m) of a £75million ($93.2m) investment for a new Center for Cancer Drug Discovery to house a world-first program of 'anti-evolution' therapies.

   
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