Targeting autophagy addiction in cancer

Abstract

Autophagy inhibition is a novel cancer therapeutic strategy in the early stages of clinical trial testing. The initial rationale for using autophagy inhibition was generated by research revealing that autophagy is upregulated in response to external stresses, including chemotherapy and radiotherapy. Combining autophagy inhibition with agents that induce autophagy as a pro-survival response may therefore increase their therapeutic efficacy. Recent research has shown that some cancer cells, particularly those driven by the K-Ras oncogene, also depend on elevated levels of autophagy for survival even in the absence of external stressors. In multiple in vitro as well as in vivo systems, oncogenic Ras-mediated transformation and tumor growth are dependent on autophagy to evade metabolic stress and cell death. These studies have subsequently led to further early phase clinical testing whether autophagy inhibition is a viable and effective strategy for targeting Ras-driven tumors. Even before the clinical results are available from these ongoing clinical trials, much work remains to optimally develop the approach of autophagy inhibition clinically; most notably reliably detecting levels of autophagy in human tumor samples, pharmacodynamics of currently available autophagy inhibitors (chloroquine and the derivative hydroxychloroquine), and new target identification and drug development.

Figure 1. Ras oncogene-induced transformation and tumorigenesis depends on autophagy induction to evade potentially lethal metabolic stress

The green dots in the orange and red cells represent autophagic puncta.

Figure 2. Future directions and challenges in autophagy inhibition

A) Large scale screening of human tumor samples and cell lines, both oncogenic Ras-driven and otherwise, for elevated basal autophagy will identify a subset of tumors that may be particularly sensitive to autophagy inhibition as a therapeutic strategy. Method development will be required to translate this aim given the limited utility of current methods for examining human tumor samples for basal autophagy. B) Pre-clinical testing of autophagy inhibition as a therapeutic strategy in autophagy dependent tumors will lead to future clinical trials. Pre-clinical model development, pharmacodynamics of current autophagy inhibitory drugs, new target identification, and new inhibitor development are all important challenges facing the field of researchers investigating autophagy inhibition. C) Ongoing and future human clinical trials employing autophagy inhibition either as monotherapy or in combination with chemotherapy or targeted therapy will test the utility of autophagy inhibition as a cancer therapeutic strategy.