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Measuring expression of the gene TJP1 could help determine which multiple myeloma (MM) patients are most likely to benefit from treatment with proteasome inhibitors (PIs), according to a study published in Cancer Cell.
Investigators found that TJP1 enhanced PI sensitivity in vitro and in vivo.
When they analyzed patient data, the team found that high TJP1 expression in patients’ MM cells was associated with a significantly higher likelihood of responding to bortezomib and a longer response duration.
“Proteasome inhibitors form the cornerstone of our standard therapy for multiple myeloma,” said study author Robert Orlowski, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“However, no biomarkers have been clinically validated that can identify patients most likely to respond to this treatment. Our findings provide a rationale for use of TJP1 as the first biomarker to select patients who are most and least likely to benefit from proteasome inhibitors.”
At the start of this study, Dr Orlowski and his colleagues examined gene-expression profiles of ANBL-6 and KAS-6/1 wild-type and bortezomib-resistant MM cells and found that TJP1 was downregulated in the resistant cells.
To further study the role of TJP1 in PI resistance, the investigators conducted experiments with RPMI 8226 and U266 MM cell lines (models that expressed high TJP1 levels) and MOLP-8 (a model that expressed low levels).
They found that knocking down TJP1 in RPMI 8226 and U266 cells with short hairpin RNA (shRNA) preserved the cells’ viability after exposure to bortezomib or carfilzomib. On the other hand, TJP1 overexpression sensitized MOLP-8 cells to the PIs.
In mice, RPMI 8226/TJP1 shRNA tumors were less sensitive to bortezomib than RPMI 8226/control tumors. And mice with MOLP-8/TJP1 shRNA tumors had a greater reduction in tumor growth after bortezomib treatment than MOLP-8/control mice.
Further investigation revealed that TJP1 modulates signaling through a pathway involving EGFR, JAK1, and STAT3. This finding supports the hypothesis that plasma cells expressing low TJP1 levels have both high EGFR/JAK1/STAT3 activity and high proteasome content.
“Therefore, these plasma cells were resistant to proteasome inhibitors,” Dr Orlowski explained. “Moreover, they demonstrated a previously unknown role for EGFR signaling in myeloma and for STAT3 in controlling the level of proteasomes in cells and, therefore, the cell’s ability to break down proteins.”
“This study allows us to identify promising future directions to overcome proteasome inhibitor resistance in patients with high signaling through the EGFR/JAK1/STAT3 pathway by offering combination therapies such as bortezomib with either the EGFR inhibitor erlotinib or a JAK1 inhibitor such as ruxolitinib.”
Finally, Dr Orlowski and his colleagues found that patients whose MM cells expressed low TJP1 levels were significantly less likely to achieve a response or benefit from bortezomib.
Patients who achieved a response after bortezomib across multiple studies had significantly higher TJP1 expression than nonresponders. And patients with the highest TJP1 expression levels had the longest time to progression.
