Kinome Signatures Can Guide Rational Combination Therapy Design

Cancer cells frequently develop resistance to single kinase inhibitors through activation of compensatory pathways that promote survival. To identify kinases whose activation promotes drug resistance, Duncan and colleagues developed a proteomics approach in which cell lysates were incubated with multiplexed beads conjugated to selective and pan-kinase inhibitors. The bound kinases were identified by mass spectrometry and drug-induced increases in binding were indicative of elevated kinase activity. Application of this method to triple-negative breast cancer (TNBC) cell lines and primary tumor samples, in which the MEK signaling pathway is elevated, revealed that multiple receptor tyrosine kinases (RTK) were activated in response to treatment with the MEK inhibitor selumetinib (AZD6244). Mechanistically, inhibition of the MEK signaling pathway promoted the proteasomal degradation of c-MYC, which subsequently led to transcriptional derepression of RTKs such as VEGFR2 and PDGFRβ. Knockdown of either of these kinases enhanced TNBC cell growth inhibition by selumetinib, indicating that this reprogramming of the kinome in response to selumetinib treatment was necessary to subvert MEK inhibition. These findings further suggested that combining selumetinib with sorafenib, a small-molecule inhibitor of both VEGFR2 and PDGFRβ, might be an effective approach in TNBC. Both were ineffective as single agents, but when combined, the 2 kinase inhibitors synergistically blocked TNBC cell growth in vitro and induced significant tumor regression in a genetically engineered TNBC mouse model. Together, these findings identify a potential therapeutic strategy for TNBC and establish a method for rational design of combination kinase inhibitor therapies that can potentially improve clinical responses.

Duncan JS, Whittle MC, Nakamura K, Abell AN, Midland AA, Zawistowski JS, et al. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 2012;149:307–21.

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