Scientists Reveal Mechanism of Action of Anticancer Drug

Pomalidomide helps treat patients with lenalidomide-resistant multiple myeloma. A team of scientists report novel findings concerning the mechanism of action of pomalidomide.

The scientists show, in their paper published in Nature Chemical Biology, that pomalidomide causes the breakdown of a protein called ARID2.

‘Pomalidomide causes the breakdown of a protein called ARID2, that promotes the "expression" of genes that are vital for the growth of multiple myeloma cancer cells.’
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ARID2 promotes the "expression" of genes (the process by which the gene code is "read out" and used to create specific proteins) that are critical for the growth of multiple myeloma cells, so breaking down ARID2 is harmful to the cancer cells and beneficial to patients.

"Our results provide new insights into the mechanisms of pomalidomide," notes Prof. Yamamoto, "and we now have a better understanding of the clinical importance of ARID2 and related proteins in the context of multiple myeloma."

To unravel how pomalidomide affects multiple myeloma cells, the scientists conducted a series of experiments involving cultured myeloma cells. Their experiments confirmed that treating the myeloma cells with pomalidomide reduced the levels of ARID2 within the cells, with greater pomalidomide concentrations and longer exposure times resulting in lower ARID2 levels.

ARID2 promotes the expression of a gene called MYC, and the resulting MYC protein is very important for the growth of myeloma cells. Unsurprisingly, the cells that had lower ARID2 levels after being treated with pomalidomide also had reduced MYC levels.

These findings offer a plausible explanation for why pomalidomide is effective at combating multiple myeloma. Interestingly, lenalidomide was not as effective as pomalidomide at reducing ARID2 levels and the expression of the MYC gene, and this may explain why some patients benefit from pomalidomide but not lenalidomide.

The scientists also showed that ARID2 expression is associated with a poor prognosis and is higher in patients with relapsed or refractory multiple myeloma, most of whom acquire resistance to lenalidomide.

The patient group with high ARID2 expression (dash line) indicated lower survival probability than the patient group with low ARID2 expression (solid line), suggesting that ARID2 is useful prognostic marker to predict overall survival periods of patients with multiple myeloma.

Multiple Myeloma / Plasma Cell Myeloma–Symptoms-Treatment-Prognosis-Support Group
Multiple Myeloma caught public attention when model turned actress Lisa Ray, who worked in Deepa Mehta’s ‘Water’ , declared that she had the incurable Multiple Myeloma.

Collectively, these results offer intriguing insights into how pomalidomide benefits patients with lenalidomide-resistant multiple myeloma, and these insights may help researchers develop new ways to treat this group of patients.

"Our findings suggest that ARID2 is a promising target for overcoming lenalidomide resistance in patients with multiple myeloma," notes Prof. Yamamoto. Armed with this knowledge, scientists can now find ways to improve survival times for patients diagnosed with this deadly form of cancer.

Source-Eurekalert