Investigating effects of copy number alterations on targeted therapy response using a conditioning-based model

Abstract

Emerging targeted therapies have shown benefits such as less toxicity and higher effectiveness in specific types of cancer treatment; however, the accessibility of these advantages may rely on sufficient understanding of mechanisms causing resistance and correct identification of suitable patients, which remain highly immature. Based on the fact that copy number alterations (CNAs) may affect expression levels and regulatory activities, CNAs are assumed to be capable of interfering with signal transduction and influence targeted drug effectiveness. Considering the mechanism of action (MOA) of trastuzumab in the ERBB2-ERK signaling pathway, a conditioning-based model in which copy number alterations (CNAs) serve as latent parents modifying signal transduction is applied. Using mathematical induction, the upstream and downstream CNAs are found to have equal influence on drug effectiveness. Two scoring functions, M-score and R-value, are further proposed to provide qualitative and quantitative information regarding the unfavorableness of a CNA on drug utility and thereby shed light on personalized therapy.