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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, marketed by US pharmaceutical giant Pfizer (NYSE: PFE) under the name of Ibrance, has been described as one of the greatest advances in women with advanced bad cancer since two decades – so it is promising to make 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 at the Institute of Cancer Research in London and the UCL Cancer Institute have found that palbociclib resistance is often caused by a protein targeted by crizotinib (marketed as Xalkori by Pfizer), which justifies the joint use of these two drugs.
Their new study, published today (July 12) in the journal Oncogene, 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 tumor cells grown in laboratory-developing tumors in mice.
MET and FAK critical molecules in the signaling pathway
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.
MET and FAK were critical molecules in the signaling pathway. The inhibitors are already in clinical trials and this idea could be tested soon.
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