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The introduction of proteasome inhibitors (PIs) into multiple myeloma (MM) treatment has substantially improved therapeutic options and survival rates. However, the development of resistance to PIs as well as serious side effects of PI treatment continue to justify the search for effective, less burdensome combination therapies. Thus, we investigated the therapeutic potential of VS-4718 (dual pPYK2- and pFAK-inhibitor) alone and in combination with the PI carfilzomib (carf) in parental human MM cell lines (pHMCLs) and PI triple-resistant HMCLs (rHMCLs). VS-4718 reduced the viability in a concentration dependent manner in all pHMCLs and the response was independent of PYK2 expression or activation. A more than additive impact of the combination therapy on survival, measured by annexin V-FITC/PI staining, was observed in 5/7 pHMCLs. Titration experiments showed that VS-4718 in combination with low and sublethal doses of carf had a specific anti-tumor effect on pHMCLs but hardly affected peripheral blood mononuclear cells. In rHMCLs, addition of VS-4718 to carf re-sensitized cells to carf and revealed a more than additive reduction in cell survival. These findings suggest that VS-4718 together with low doses of carf could be an effective and low-toxic combination in MM, including PI-resistant, relapsed/refractory MM.

Multiple myeloma (MM) is a hematological malignancy whose curability is greatly challenged by recurrent patient relapses and therapy resistance. We have previously proposed the high expression of ADAM8 , ADAM9 and ADAM15 (A Disintegrin And Metalloproteinase 8/9/15) as adverse prognostic markers in MM. This study focused on the so far scarcely researched role of ADAM8/9/15 in MM using two patient cohorts and seven human MM cell lines (HMCL). High ADAM8 / 9 / 15 expression was associated with high-risk cytogenetic abnormalities and extramedullary disease. Furthermore, ADAM8 / 15 expression increased with MM progression and in relapsed/refractory MM compared to untreated patient samples. RNA sequencing and gene set enrichment analysis comparing ADAM8 / 9 / 15 high/low patient samples revealed an upregulation of proliferation markers and proliferation-associated gene sets in ADAM8 / 9 / 15 high patient samples. High ADAM8 / 9 / 15 expression correlated with high Ki67 and high ADAM8 / 15 expression with high MYC protein expression in immunohistochemical stainings of patient tissue. Conversely, siRNA-mediated knockdown of ADAM8 / 9 / 15 in HMCL downregulated proliferation-related gene sets. Western blotting revealed that ADAM8 knockdown regulated IGF1R/AKT signaling and ADAM9 knockdown decreased mTOR activation. Lastly, high ADAM8 / 9 / 15 expression levels were verified as prognostic markers independent of Ki67/MYC expression and/or high-risk abnormalities. Overall, these findings suggest that ADAM8/9/15 play a role in MM progression and proliferation signaling.

High expression of the receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) and RTK mutations are associated with high-risk/worse prognosis in multiple myeloma (MM). Combining the pIGF1R/pINSR inhibitor linsitinib with the proteasome inhibitor (PI) bortezomib seemed promising in a clinical trial, but IGF1R expression was not associated with therapy response. Because the oncogenic impact of IGF1R mutations is so far unknown, we investigated the functional impact of IGF1R mutations on survival signaling, viability/proliferation and survival response to therapy. We transfected four human myeloma cell lines (HMCLs) with IGF1RWT, IGF1RD1146N and IGF1RN1129S (Sleeping Beauty), generated CRISPR-Cas9 IGF1R knockouts in the HMCLs U-266 (IGF1RWT) and L-363 (IGF1RD1146N) and tested the anti-MM activity of linsitinib alone and in combination with the second-generation PI carfilzomib in seven HMCLs. IGF1R knockout entailed reduced proliferation. Upon IGF1R overexpression, survival signaling was moderately increased in all HCMLs and slightly affected by IGF1RN1129S in one HMCL, whereby the viability remained unaffected. Expression of IGF1RD1146N reduced pIGF1R-Y1135, especially under serum reduction, but did not impact downstream signaling. Linsitinib and carfilzomib showed enhanced anti-myeloma activity in six out of seven HMCL irrespective of the IGF1R mutation status. In conclusion, IGF1R mutations can impact IGF1R activation and/or downstream signaling, and a combination of linsitinib with carfilzomib might be a suitable therapeutic approach for MM patients potentially responsive to IGF1R blockade.