Sci Adv: A New Mechanism of Multiple Myeloma's Resistance to Immunomodulators

Editor-in-Chief | Enzyme Multiple Myeloma is an incurable blood cancer.
At present, some newly developed drugs, such as proteasome inhibitors [1], immunomodulators [2-4], monoclonal antibodies [5], etc.
Improve the patient's treatment effect
.

Immunomodulators (IMiDs) can directly kill myeloma cells and can enhance the body's anti-tumor immunity
.

Multiple research groups have found that the anti-myeloma activity of IMiDs is mainly due to its ability to directly bind to the CRBN protein in the cell as a molecular glue, thereby enhancing the activity of CRL4CRBN ubiquitin ligase, and then specifically degrading the transcription factor IKZF1, which is important for B cell survival.
And IKZF3 [6,7]
.

However, most patients in the clinic will develop resistance to IMiDs during treatment, which will lead to disease recurrence
.

At present, many studies on IMiDs resistance are focused on CRBN expression regulation and mutations, but many patients show resistance in clinics, and they do not have CRBN dysfunction, which indicates that there are other potential mechanisms
.

Recently, the Kenneth C.
Anderson team at the Dana-Farber Cancer Institute at Harvard Medical School (Dr.
Jiye Liu and Dr.
Teru Hideshima as co-first authors) published a titled ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow in Science Advances.
Research papers on microenvironment
.

The paper described in detail the role and mechanism of ERK signaling pathway in myeloma drug resistance caused by the bone marrow microenvironment of multiple myeloma
.

Through CRISPR-Cas9 genome-wide knockout screening, the researchers found that in addition to the genes in the CRBN pathway, the knockout of TRAF2 gene showed strong drug resistance
.

Subsequent verification found that the resistance caused by TRAF2 knockout has nothing to do with the degradation of CRBN-IKZF1/3
.

The expression of TRAF2 in patients with drug-resistant relapse in myeloma patient samples was also significantly lower than that in newly diagnosed patients
.

In subsequent studies, researchers found that TRAF2 knockout can activate the non-canonical NF-κB signaling pathway and the downstream ERK signaling pathway
.

In vivo and in vitro experiments inhibiting the ERK signaling pathway can significantly enhance the sensitivity of myeloma cells to IMiDs
.

In patients, the bone marrow microenvironment plays an important role in the drug sensitivity of myeloma
.

The researchers found that TNF-α secreted by bone marrow stromal cells can degrade TRAF2 through ubiquitination, thereby activating the non-canonical NF-κB signaling pathway and the downstream ERK signaling pathway to induce myeloma cells to be resistant to IMiDs
.

Similarly, inhibiting the ERK signaling pathway can significantly overcome the IMiDs resistance caused by the myeloma microenvironment
.

In conclusion, the researchers confirmed through in vivo and in vitro experiments that the immune microenvironment of myeloma can degrade TRAF2 through ubiquitination and activate the downstream ERK signaling pathway, leading to resistance to IMiDs.
The mechanism has nothing to do with CRBN-IKZF1/3
.

These results can provide guidance for the clinical application of ERK signaling pathway inhibitors to overcome the resistance of IMiDs, and improve the clinical treatment effect of myeloma patients
.

Original link: https://advances.
sciencemag.
org/lookup/doi/10.
1126/sciadv.
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