The combination of targeted breast and lung cancer drugs could help overcome resistance to treatment

A new study shows that bad cancer and lung cancer drugs could be used together to overcome treatment resistance in many types of tumors.

Scientists found that when palbociclib, an anticancer drug in the bad, was badociated with crizotinib, a lung cancer drug, the combination of two drugs was significantly more effective against cancer cells in the laboratory than one or the other. other drugs used alone.

Palbociclib has been described as one of the greatest advances in women with advanced bad cancer for 20 years. It is therefore promising to make the treatment even more effective.

The new findings also suggest that the combined approach could expand the clinical use of palbociclib – and other drugs that work in the same way – beyond bad cancer to also include many other types of tumors.

Scientists from the Institute of Cancer Research of London and the UCL Cancer Institute have discovered that palbociclib resistance is often caused by a crizotinib-targeted protein, which justifies the joint use of these two drugs.

Their new study is published today (Friday) in the journal oncogenic and was funded by Wellcome.

Palbociclib is part of a group of drugs currently used to treat patients with hormone receptor-positive bad cancer by blocking the function of two proteins, CDK4 and CDK6, that promote tumor cell division. and the progression of cancer.

However, cancers can become resistant to palbociclib by activating a cognate molecule called CDK2, capable of driving cell division in the absence of CDK4 / 6.

In this new study, researchers found that CDK2 could compensate for inhibition of CDK4 / 6 in cancer cells by signaling via a cellular control pathway involving key MET and FAK molecules.

Based on this discovery, the researchers discovered that the combination of a CDK4 / 6 inhibitor, such as palbociclib, with a crizotinib – which blocks the activity of the MOS – has created a combined treatment much more effective than a single drug against cancer cells grown in the laboratory or in humans. tumors developing in mice.

The combined agents have synergized not only to block the division of cancer cells, but also to induce senescence, a condition in which cells are thought to stop growing and dividing, but without cell death.

The researchers have obtained promising results on cancer cells derived from different organs of the body – from the bad and lung to the intestine – indicating that there is a potential for extension of the cancer. # 39; clinical use of palbociclib and other CDK4 / 6 inhibitors beyond bad cancer, for a larger number of patients. .

To reveal the underlying mechanism of resistance, the researchers conducted a systematic search using robotics and sophisticated imaging to identify the mode of activation of CDK2 in order to allow cells to evade the inhibitors of CDK4 / 6.

They discovered that MET and FAK are essential molecules in the signaling pathway used by cancer cells to survive and develop resistance to palbociclib treatment.

The researchers hope that their findings can be pbaded on to patients – first by badessing the safety and efficacy of the combination of CDK4 / 6 inhibitors such as palbociclib with MET inhibitors, such as crizotinib.

It may be possible to develop laboratory tests to identify patients who might benefit from using crizotinib in this way.

And, a little further in the future, researchers also point to the possibility that their research suggests that the combination of CDK4 / 6 inhibitors with FAK blocking drugs may be even more effective and more generally applicable.

Indeed, their results show that FAK is a critical node in cellular circuits leading to an undesirable activation of CDK2.

FAK inhibitors are already undergoing clinical trials and this idea could therefore be tested soon.

The combination of targeted drugs with different mechanisms of action is one of the central strategies that the Institute for Cancer Research (ICR) is pursuing as part of an innovative research program aimed at combating cancer capacity to adapt, evolve and become resistant to drugs.

ICR, a charity and research institute, raises £ 15 million from a £ 75 million investment in a new cancer research center to offer an innovative program of anti-cancer therapies -evolution".

The co-leader of the study, Professor Paul Workman, general manager of the London Cancer Institute, said:

"The ability of cancer to adapt, evolve and become drug-resistant is the main challenge we face in creating more effective treatments for the disease." In this study, we sought to understand exactly how showed resistance to an important family of bad cancer drugs, can stay one step ahead of cancer.

"We have demonstrated the possibility of combining two precision bad cancer and lung cancer drugs to create a two-pronged attack that rids cancer cells of their resistance, and we need to do more to understand the full potential of cancer. combination therapy to increase the effectiveness of these drugs, but the approach seems very promising and could be effective against several types of cancer. "

Professor Sibylle Mittnacht, Professor of Molecular Cancer Biology at the UCL Cancer Institute, co-head of the study, said:

"Our evidence shows that existing drugs could be used to overcome resistance to the treatment of a common form of bad cancer in women.

"In addition, the use of a current bad cancer drug with these other drugs could be a promising new avenue for the treatment of lung cancer and several other cancers."

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