Durability of Kinase-Directed Therapies—A Network Perspective on Response and Resistance

Abstract

Protein kinase-directed cancer therapies yield impressive initial clinical responses, but the benefits are typically transient. Enhancing the durability of clinical response is dependent upon patient selection, using drugs with more effective pharmacology, anticipating mechanisms of drug resistance, and applying concerted drug combinations. Achieving these tenets requires an understanding of the targeted kinase's role in signaling networks, how the network responds to drug perturbation, and patient-topatient network variations. Protein kinases create sophisticated, malleable signaling networks with fidelity coded into the processes that regulate their presence and function. Robust and reliable signaling is facilitated through network processes (e.g., feedback regulation, and compensatory signaling). The routine use of kinase-directed therapies and advancements in both genomic analysis and tumor cell biology are illuminating the complexity of tumor network biology and its capacity to respond to perturbations. Drug efficacy is attenuated by alterations of the drug target (e.g., steric interference, compensatory activity, and conformational changes), compensatory signaling (bypass mechanisms and phenotype switching), and engagement of other oncogenic capabilities (polygenic disease). Factors influencing anticancer drug response and resistance are examined to define the behavior of kinases in network signaling, mechanisms of drug resistance, drug combinations necessary for durable clinical responses, and strategies to identify mechanisms of drug resistance.

Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance

“…Cellular analyses are routinely used to characterize drug performance because isolated cells capture a subset of the biological complexity expected in the clinic (30). A limitation of this approach is that patients have a multitude of cellular environments with unique complements of expressed proteins that create a broad spectrum of signaling network architectures.…”

“…A limitation of this approach is that patients have a multitude of cellular environments with unique complements of expressed proteins that create a broad spectrum of signaling network architectures. As such, it is challenging to map clinical phenotypes of drugs to molecular processes using cell culture (30). For drugs that target intracellular signaling proteins (e.g., serine/threonine protein kinases), pharmacodynamic markers (e.g., pRb phosphorylation) can be modified by multiple enzymes obscuring the molecular mechanism of drug action.…”

“…Taken together, defining the molecular interactions of CDK drugs enables a better understanding of clinical responses and clinical utility. This knowledge provides a foundation for the rational design of future generations of CDKdirected drugs that will counter the expected drug resistance typically found with kinase-directed therapies (30).…”

“…The current study explores the range of biology impacted by CDK-targeted drugs using suites of biochemical, cellular, and structural assessments. The nexus of these approaches yields a nonclinical description for the range of activities the CDK drugs that is consistent with clinical responses and facilitates the discovery of next-generation therapies for the expected drug resistance (30).…”

Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics

“…Despite strong initial responses, cancer cells frequently develop resistance to kinase inhibitors by acquiring active site mutations or exploiting the intrinsic redundancy of kinase signaling pathways (44). This shift to alternative kinase signaling nodes occurs through a process termed “adaptive kinome reprogramming’ resulting in transcriptional up-regulation and activation of compensatory kinases and their adaptor proteins.…”