A New View of Pathway-Driven Drug Resistance in Tumor Proliferation. (May 2017)

• Record Type: Journal Article
• Authors: Nussinov, Ruth; Tsai, Chung-Jung; Jang, Hyunbum
• Is Part Of: Trends in pharmacological sciences. Volume 38:Number 5(2017)
• Page Start: 427
• Page End: 437
• Publication Date: 2017-05
• Subjects: KRAS -- K-Ras -- RAS -- MAPK -- PI3K -- signaling pathways; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2017.02.001
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Defeating drug resistance in tumor cell proliferation is challenging. We propose that signaling in cell proliferation takes place via two core pathways, each embodying multiple alternative pathways. We consider drug resistance through an alternative proliferation pathway – within the same or within the other core pathway. Most drug combinations target only one core pathway; blocking both can restrain proliferation. We define core pathways as independent and acting similarly in cell-cycle control, which can explain why their products (e.g., ERK and YAP1) can substitute for each other in resistance. Core pathways can forecast possible resistance because acquired resistance frequently occurs through alternative proliferation pathways. This concept may help to predict the efficacy of drug combinations. The selection of distinct combinations for specific mutated pathways would be guided by clinical diagnosis. Trends: Owing to the expected emergence of tumor cell drug resistance, to maximize survival benefits, combinatorial drug treatments are routinely employed in chemotherapeutics. Blockade of oncogenic signaling either by targeting the same pathway or a combination of pathways accomplishing the same cellular function is a frequently contemplated strategy. To counteract pathway-based resistance, efforts focus either downstream of the protein, making it harder to achieve pathway reactivation; however, an acquired alternative pathway can take over – as in the case of ERK5 pathway bypassing blockade of ERK1/2 or MEK1/2. By contrast, upstream blockade can elicit downstream pathway activation. Drug combinations to block proliferation pathways are in development, but the fundamental combinatorial principle is still elusive.