Combinatorial drug screening identifies synergistic co-targeting of Bruton’s tyrosine kinase and the proteasome in mantle cell lymphoma

Bruton’s tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib

“…Combinatorial drug screens have identified the proteasome inhibitors bortezomib and carfilzomib as having robust in vitro cytotoxic synergies with ibrutinib in MCL and DLBCL cell lines and primary samples from patients [Axelrod et al 2014;Dominici et al 2013;Zhang et al 2013;Dasmahapatra et al 2013]. In MCL-bearing SCID-hu mice, the combination of ibrutinib with carfilzomib increased survival threefold compared with either agent administered alone [Axelrod et al 2014]. Carfilzomib's superior safety profile and greater apoptotic activity (compared with bortezomib) have led to the design of a phase I/II clinical trial evaluating it in combination with ibrutinib in R/R MCL.…”

Applications of Systems Biology to Identify Mechanisms of Adaptive Response to Targeted Single and Combinatorial Drug Treatment in Cancer

“…This drug has an exceptional overall response rate of 68% in patients with relapsed or refractory MCL, and 83% in patients with relapsed or refractory CLL (Byrd et al, 2013;Wang et al, 2013). The highest response rates demonstrated by a single agent therapy in MCL or CLL (Axelrod et al, 2014a). However, as with melanoma, response to single agent therapy is not durable, and single agent therapy tends to induce adaptive responses that lead to drug resistance (Garraway and Jänne, 2012;Gioeli et al, 2011).…”

“…In our studies, we have taken a synthetic lethal approach to identify drug combinations that cause synergistic cytotoxicity in a number of cancer types, utilizing the Bliss score of independence as a measure of synergy (Axelrod et al, 2014a(Axelrod et al, , 2014c(Axelrod et al, , 2014bRoller et al, 2012). In our melanoma screen of 12 BRAF V600E mutants, we identified the combination of the vemurafenib analog PLX4720 in combination with lapatinib as being a potent therapy that induces synergistic cytotoxicity in six of the twelve lines assayed.…”

“…Following the screening strategy utilized effectively in melanoma, the Weber lab was able to identify a number of drugs that when combined elicit a synergistic response in preclinical models of CLL and MCL (Axelrod et al, 2014a). Ibrutinib combined with ABT--199, an inhibitor of BCL2; or carfilzomib, or bortezomib, both of which are proteasome inhibitors, showed cytotoxic synergy.…”

“…Ibrutinib, a targeted therapy that inhibits Bruton's Tyrosine Kinase (BTK), a component of the BCR signaling pathway, shows overall response rate of 68% in patients with relapsed or refractory MCL, and 83% in patients with relapsed or refractory CLL (Axelrod et al, 2014a). As with melanoma, single agent therapy is not durable for CLL and MCL, as it induces adaptive responses, however, drug combinations that block adaptive signaling responses may increase both progression--free survival and overall survival in MCL Pott et al, 2010).…”