Fellow's research: Two chemotherapy drugs act together to degrade a key onco-protein in multiple myeloma
05 Mar 2020
Dr. Vikram Mathews, Senior Fellow, Christian Medical College, Vellore
Our recently published study describes the molecular details of how two chemotherapy drugs, lenalidomide and bortezomib, act together to degrade a key onco-protein in multiple myeloma. This study also shows that the efficacy of this treatment regimen can be further improved by combining the two drugs with the anti-cancer drug, daratuzumab.
Multiple myeloma (MM) represents a broad spectrum of B-cell cancers and accounts for approximately 13 percent of all blood cancers. In the past decade, introduction of drugs which can modulate immune system response (immunomodulatory drugs -IMiDs), along with proteasome inhibitors, has been shown to improve the clinical outcomes without increased toxicity in patients with this disease.
Recent evidence suggest that the molecular mechanism of action of Lenalidomide – an immunomodulatory drug – in multiple myeloma (MM) depends upon its ability to interact with a protein named ‘cereblon’. This protein in turn sends two key proteins (Ikaros and Aiolos) known to be involved in the pathology of this disease into degradation via proteasome machinery (protein degrading machinery). Degradation of these proteins was found out to be the key mechanism by which lenalidomide induced cancer cell death in multiple myeloma.
Naturally, when this proteasome machinery is blocked, it interrupts the degradation of these key proteins. Hence, in theory, a proteasome inhibitor should never be used along with an immuno-modulatory drug to treat multiple myeloma. However, in the clinic, these two drugs had been shown to have a superior effect when combined in patients. We aimed to study possible reasons for this paradox – how these two drugs act together to bring a superior effect – and also the fate of Ikaros when this combination is used.
We observed in vitro that these two drugs indeed act together to induce cell death in two different types of cancer cells. Interestingly, the key proteins (Ikaros and aiolos) were degraded even when we combined both the drugs. However, the degradation did not follow the canonical protein degrading pathways.
We identified that when we combined these two drugs, there was increased calcium flux into the cells, which led to the activation of specific proteases (protein-cleaving proteins). These proteases called ‘calpains’ can initiate the degradation of Ikaros. Apart from calpains, other non-specific proteases such as caspases, normally activated during cell death process, also cleaved Ikaros proteins. Inhibiting these proteases resulted in accumulation of Ikaros. Thus, we identified an alternative pathway where the key protein can be degraded even when when the combination of these two drugs used.
We also noted that this combination increased the expression of CD38, a cell surface protein which multiple myeloma cells overexpress. CD38 has recently gained attention due to availability of an antibody (daratuzumab) that binds to it and can be used to treat relapsed and refractory myeloma. Our findings suggest that adding this antibody in combination with lenalidomide and bortezomib could further improve the efficacy of this treatment regimen for multiple myeloma.
Combination lenalidomide/bortezomib treatment synergistically induces calpain-dependent Ikaros cleavage and apoptosis in myeloma cells. Saravanan Ganesan, Hamenth Kumar Palani, Nithya Balasundaram, Sachin David, Anup J. Devasia, Biju George, and Vikram Mathews. Molecular Cancer Research (2020).