Scientists Unveil New Target to Stop Bortezomib Resistance in Patients With Multiple Myeloma

Scientists have found a potential new pathway to stop bortezomib resistance in patients with multiple myeloma (MM).

In a new study published in OncoTargets and Therapy, investigators from Central South University in China, write that induced expression of PH domain leucine-rich repeat protein phosphatase (PHLPP) may help boost bortezomib (BTZ) sensitivity in in MM cells by activating the autophagy pathway.

BTZ has been shown to boost both overall survival rates and recurrence-free survival rates in patients with MM. However, some patients experience primary or acquired resistance to the drug, making them likely to have a recurrence of the disease.

Corresponding author Yunfeng Fu, PhD, and colleagues note that PHLPP has been known to play a role in the chemoresistance of a number of cancers. Thus, they decided to investigate whether or not it had an effect in MM.

To do so, they used MM cells from 3 patients, as well as BTZ-resistant MM cells from a cell bank and compared levels of PHLPP and lysosome-associated membrane protein 2 (LAMP2). They then experimented with differing levels of PHLPP and LAMP2.

“We found that LAMP2 and PHLPP expression levels in BTZ-resistant plasma cells of human samples were downregulated compared with BTZ-sensitive samples,” said the study authors.

Researchers suggest that strategies could be developed to use BTZ in combination with existing therapies. They additionally note that MM cells produce insulin-like growth factor 1 (IGF-1). BTZ resistance has been associated with heightened levels of IGF-1 and its receptor.

“The IGF-1R inhibitor OSI-906 can increase the cytotoxicity of BTZ in MM cells, and PI3K and AKT are the downstream targets of IGF1,” they write. “AKT inhibition also causes BTZ-resistant cell death,” said the study authors.

Thus, they said OSI-906 may be helpful if used in combination with BTZ in patients with resistance to BTZ.

Fu and colleagues also note that scientists might benefit from further exploration of the interactions between PHLPP, AKT, and the protein complex NF-κB, writing that these interactions might have implications for cell apoptosis in patients with MM.

Meanwhile, significant evidence exists supporting the role of lower LAMP2 expression in drug resistance. For instance, lower LAMP2 was associated with lower survival rates and loss of sensitivity to treatment in patients with acute myeloid leukemia. Similar findings were reported in lung cancer cells.

In the case of MM, the investigators also found a correlation between LAMP2 levels and drug resistance, though they found no such link with LAMP1. The team also reported that it appeared to be the variant LAMP2A, but not LAMP2B, that was associated with BTZ resistance.

“These results indicated that LAMP2A is the executor in the regulation of CMA [chaperone-mediated autophagy] in MM cells,” Fu and colleagues write. “Re-expression of LAMP2 in LAMP2-deficient BTZ-resistant MM cells restored [CMA], highlighting the key role of LAMP2 in this process.”

Understanding how exactly LAMP2 and PHLPP interact in BTZ resistance will require additional research, but the study authors suggest 1 hypothesis.

“Our results showed that PHLPP interacted with LAMP2, and LAMP2 is required for PHLPP-mediated autophagy,” they write. “It would be reasonable that PHLPP acts primarily to interact with and stabilize LAMP2 on the lysosomes to promote the fusion between autophagosome and lysosome (ie, formation of autolysosome) and thereby removal of autophagosome.”

They conclude that rescuing PHLPP in patients with MM and BTZ resistance should be considered as a strategy to reverse resistance.

Reference:

Liu X, Li C, Fu Y, et al. PHLPP sensitizes multiple myeloma cells to bortezomib through regulating LAMP2 [published online January 14, 2020]. Onco Targets Ther. doi:10.2147/OTT.S237343.