Timothy J. Stuhlmiller

TL;DR: To make the tumor response to single kinase inhibitors durable, the adaptive kinome response itself must be inhibited, and combining inhibitors of kinases and chromatin readers prevents kinome adaptation by blocking transcription, generating a durable response to lapatinib, and overcoming the dilemma of heterogeneity in the adaptive response.

TL;DR: Widespread transcriptional adaptation to pharmacologic MEK inhibition was observed in TNBC patient tumors, and pharmacologic targeting of P-TEFb members in conjunction with MEK inhibited by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance.

TL;DR: Understanding the breadth of adaptive reprogramming responses to specific targeted kinase inhibition will be critical to develop appropriate combination therapies for durable clinical responses to single-agent kinase inhibitors.

TL;DR: Drug potency influences PI3K/MEK inhibitor-induced target inhibition, adaptive kinome reprogramming, efficacy, and synergy, and suggest that combination therapies with highly potent, brain-penetrant kinase inhibitors will be required to improve patient outcomes.

TL;DR: GSK2801 blocks BRD2-driven transcription in combination with BET inhibitor and induces apoptosis of TNBC by a combinatorial suppression of ribosomal DNA transcription and ETS-regulated genes.