Chemoresistance in Mesothelioma: The Role of Genetics

A team of Swiss and German researchers have a theory about why so many mesothelioma patients experience chemoresistance. 

Chemotherapy is the standard first-line treatment for asbestos cancer. But fewer than half of patients respond to it. 

The new study suggests that this may have to do with an alteration on the BAP1 gene. Medicine cannot change a person’s underlying genetics. But knowing who is likely to experience chemoresistance could help patients and doctors choose the most effective treatments. 

BAP1 Expression and Mesothelioma

BAP1 stands for BRCA1 associated protein-1. People who have an inherited mutation of this gene produce less of the BAP1 protein. This seems to increase their risk for malignant mesothelioma and several other conditions. People with BAP1 loss are also more likely to develop moles called atypical spitz nevi and a rare type of eye cancer. 

Most patients with this genetic anomaly never know it. Genetic testing for BAP1 loss is not common and doctors cannot tell if a patient has it by examination. But studies suggest that it could affect more than half of mesothelioma patients. 

On the other hand, chemoresistance – a failure to respond to chemotherapy –  is common among people with pleural mesothelioma. But chemotherapy is still the main treatment for this rare cancer. Most patients receive a combination of Alimta and the platinum drug cisplatin. 

Unfortunately, these drugs only work for about 40 percent of patients. Chemoresistance is one reason that so many mesothelioma patients die within a year of diagnosis. 

The Link Between Chemoresistance and BAP1 Loss

Doctors at University Hospital Zurich in Switzerland and University Hospital Frankfurt in Germany led the new study. It was a retrospective study. That means that they looked at past patient records to find answers. 

The team looked for patients with resectable pleural mesothelioma and available tumor samples for testing. All patients had first-line treatment with chemotherapy, followed by surgery. 

In every case, if a patient had BAP1 loss, they also had chemoresistance. 

“In a training cohort of MPM patients (n=28), mutations or deletions of BAP1 each predicted resistance to chemotherapy in primary MPM patients,” writes lead author Kathrin Oehl. 

The researchers then confirmed the results in 39 other mesothelioma patients and on mesothelioma cells in the lab. In both cases, cells with a loss of BAP1 showed chemoresistance. The researchers theorize that BAP1 loss may protect the cancer cells by inhibiting apoptosis or natural cell death.

Dr. Oehl and her colleagues conclude that BAP1 testing could help doctors and patients make more personalized mesothelioma treatment choices. 

“Alterations in BAP1 in MPM were a negative predictor for response to chemotherapy and could possibly be used as a companion biomarker for treatment decision,” concludes the report. 

Source:

Oehl, K, et al, “Alterations in BAP1 are Associated with Cisplatin Resistance Through Inhibition of Apoptosis in Malignant Pleural Mesothelioma (MPM)”, February 5, 2021, Online ahead of print, https://clincancerres.aacrjournals.org/content/early/2021/02/04/1078-0432.CCR-20-4037