Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure

Abstract

A key goal of cancer therapeutics is to selectively target the genetic lesions that initiate and maintain cancer cell proliferation and survival. While most cancers harbor multiple oncogenic mutations, a wealth of preclinical and clinical data supports that many cancers are sensitive to inhibition of single oncogenes, a concept referred to as 'oncogene addiction'. Herein, we describe the clinical evidence supporting oncogene addiction and discuss common mechanistic themes emerging from the response and acquired resistance to oncogene-targeted therapies. Finally, we suggest several opportunities toward exploiting oncogene addiction to achieve curative cancer therapies.

Keywords: feedback; oncogene addiction; oncogenic shock; targeted therapy.

Figure 1. Common mechanisms of resistance to oncogene-targeted therapeutics

(A) Second-site mutations can reinstate oncogene function while abrogating inhibitor activity, as exemplified by BCR-ABL gatekeeper mutations as an inhibitor resistance mechanism. (B) Mutations in oncogene pathway components can reinstate pathway signaling despite continued oncogene inhibition, as exemplified by MAP2K1 mutations as a resistance mechanism for BRAF inhibitors. (C) Mutational or non-mutational activation of bypass signaling pathways can render cancer cells independent of the original oncogene, as exemplified by MET activation as a resistance mechanism for EGFR inhibition.

Figure 2. Oncogenic shock versus feedback reactivation of growth factor receptor signaling

(A) Many oncogenes actively suppress growth factor receptor (GF-R)-dependent signaling in addition to activating oncogenic pathway signaling. (B) Oncogenic shock may predominate when GF-R survival signaling is slow to reinstate after oncogene inhibition (tortoise), creating a window where cells have no prosurvival signals. (C) Bypass resistance may predominate when GF-R responsiveness is quickly reactivated upon oncogene inhibition (hare).