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Jagged1/2 and drug resistance in multiple myeloma
Figure 8. Mechanism underlying Notch ability to promote drug resistance in multiple myeloma (MM) microenvironment. Jagged1/2 overexpression in MM cells causes hyperactivation of Notch signaling in the bone marrow (BM) milieu, which, in turn, promotes drug resistance by modifying both MM cell and BM stromal cell (BMSC) behavior. Indeed, (1) Notch activation in MM cell triggered by Jagged1/2 through homotypic interactions sustains resistance to drug-induced apoptosis in different ways. Notch can (2) promote the expression of the pro-survival factors BCL2, Survivin, and ABCC1 and the chemokine receptor CXCR4; (3) up-regulates HES1, which in turn inhibits the expression of the pro-apoptotic protein Noxa; (4) promotes the expression of integrin αvβ5, thus enhancing MM cell adhesion to vit- ronectin. (5) MM-derived Jagged1/2 may also activate Notch in BMSC, (6) boosting its ability to produce SDF1α, which in turn, by activating CXCR4 signaling in MM cell, promotes the expression of the anti-apoptotic factors BCL2, Survivin, and ABCC1, improving MM cell pharmacological resistance. On the other hand, (7) BMSC activate the Notch pathway in MM cells through their basal expression of Jagged1 and Dll4, (8) promoting the expression of cytochrome P450 and p21, thereby sup- porting MM cell resistance to therapy.
Indeed, MM cell-derived Jagged1 and 2 may switch on Notch signaling in tumor and non-tumor BMSC by trig- gering Notch signaling, activating MM cell anti-apoptotic background, increasing SDF1α level in the BM, and, final- ly, resulting in supporting MM cell resistance to standard- of-care drugs (Figure 8).
Overall, our findings provide the proof-of-principle that selective targeting of Jagged ligands in MM cells can restore tumor cell sensitivity to therapy, laying the foun- dation for the development of combined low-toxic thera- peutic options to restore drug sensitivity and overcome fatal drug resistance of relapsing MM patients. Recently, inhibitory small molecules30 or neutralizing antibodies49 directed to inhibit the activation of Notch signaling medi- ated by Jagged ligands have been developed. This prompt- ed us to confirm the translational potential of our results by testing the anti-tumor effect of an inhibitory small mol- ecule developed in our laboratory, IGOR1, which was directed to uncouple Notch-Jagged interaction.30 In vitro results showed that IGOR1 had the ability to increase MM cell pharmacological response, with higher efficacy if combined with Melph and Len.
The importance of our results stems from the evidence that a Jagged-tailored therapy might represent a more suit- able clinical approach to achieve the inhibition of Notch signaling in the BM of MM patients. Indeed, it lacks the potential adverse effects of pan-Notch blockade obtained with g-secretase inhibitors (GSI), that provided promising results in an in vivo MM model by increasing the chemotherapeutic effect of doxorubicin and melphalan,24 but that were associated with severe gastrointestinal toxi- city due to intestine metaplasia.50,51
Funding
This study was supported by grants from Associazione Italiana Ricerca sul Cancro, AIRC Investigator Grant to RC (20614) and AN (16722), My First Grant to AP (18741); Fondazione Italiana per la Ricerca sul Cancro to MC (post-doc- toral fellowship 18013) and ET (post-doctoral fellowship 19370); Università degli Studi di Milano to RC (Linea 2B- 2017 - Dept. Health Sciences), to NP (post-doctoral fellowship type A), SG, MTP and EL (PhD fellowship in Molecular and Translational Medicine), DG (PhD fellowship in Experimental Medicine).
References
1. Kumar SK, Rajkumar V, Kyle RA, et al. Multiple myeloma. Nat Rev Dis Primers. 2017;3:17046.
2. Nijhof IS, van de Donk N, Zweegman S, Lokhorst HM. Current and New Therapeutic Strategies for Relapsed and Refractory Multiple Myeloma: An Update. Drugs. 2018;78(1):19-37.
3. Manier S, Sacco A, Leleu X, Ghobrial IM,
Roccaro AM. Bone marrow microenviron- ment in multiple myeloma progression. J Biomed Biotechnol. 2012;2012:157496.
4. Chiaramonte R, Basile A, Tassi E, et al. A wide role for NOTCH1 signaling in acute leukemia. Cancer Lett. 2005;219(1):113-120.
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