Unblinding the watchmaker: cancer treatment and drug design in the face of evolutionary pressure

ABSTRACT

Introduction

Death due to cancer is mostly associated with therapy ineffectiveness, i.e. tumor cells no longer responding to treatment. The underlying dynamics that facilitate this mutational escape from selective pressure are well studied in several other fields and several interesting approaches exist to combat this phenomenon, for example in the context of antibiotic-resistance in bacteria.

Areas covered

Ninety percent of all cancer-related deaths are associated with treatment failure. Here, we discuss the common treatment modalities and prior attempts to overcome acquired resistance to therapy. The underlying molecular mechanisms are discussed and the implications of emerging resistance in other systems, such as bacteria, are discussed in the context of cancer.

Expert opinion

Reevaluating emerging therapy resistance in tumors as an evolutionary mechanism to survive in a rapidly and drastically altering fitness landscape leads to novel treatment strategies and distinct requirements for new drugs. Here, we propose a scheme of considerations that need to be applied prior to the discovery of novel therapeutic drugs.

KEYWORDS:

• Cancer
• dynamic treatment
• fitness landscape steering
• mutational escape

Article highlights

• Current cancer therapies often fail to prevent resistance and recurrence. Indeed, 90% of the annual 10 million cancer-related deaths are due to therapy failure.

• Mutational escape, and other forms of induced alterations, from therapy-mediated selective pressure leads to treatment resistance.

• Cellular stress can be managed reducing the risk of mutational escape. To do so successfully requires the culling of the dominant cancer cell population without attempting to drive them to extinction.

• Combining several treatment concepts, such as adaptive therapy and complex drug combinations, can allow for fitness landscape steering, a new approach in cancer management. Here, the aim is not only to predict the (epi)genetic basis for resistance, but actively to manage the emergence of such a feature.

• Successful dynamic treatment of cancer calls for combining several different approaches, such as repurposing of existing drugs, drugs specifically designed for combination therapies or substances which can increase the likelihood of which route towards mutation escape will be taken.

This box summarizes key points contained in the article.

Acknowledgments

All authors are grateful to Sara E Barry for her critical reading of an earlier version of our manuscript. Figures were created with BioRender.com

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

H Strobel gratefully acknowledges her funding by the Förderkreis für tumor‐und leukämiekranke Kinder Ulm e.V.; S Konig was supported by The Experimental Medicine Program of the International Graduate School in Molecular Medicine Ulm of Ulm University, while H Strobel also recognizes the School’s assistance.