The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. It is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors.
Use the dropdown menu or ‘Previous’ and ‘Next’ buttons to navigate the list.
A. Cipponi et al. Science 05 Jun 2020: Vol. 368, Issue 6495, pp. 1127-1131
“This paper provides evidence that cancer cells (alike bacteria) active adaptive mutability to escape targeted therapies.” Alberto Bardelli, EACR Board Member
Summary of the findings
Genetic variability is central to adaptability and evolution of human cancer.
Mutagenesis may occur incrementally or in transient bursts, triggered in response to environmental or pharmacological pressures, when genetic diversity is most needed to create evolutionary opportunities.
Conserved mechanisms underpinning stress-induced mutagenesis (SIM) have been extensively described in microorganisms. Analogous processes may underpin progression and therapeutic failure in human malignancies.
We developed in vitro model systems of intense drug selection and we undertook a genome-wide functional screen to identify common mechanisms driving SIM. These studies implicate the MTOR signaling pathway in mediating a stress-related repression of accurate DNA repair, generating new mutational landscapes which facilitate the emergence of resistance to targeted anticancer agents (Figure 1).
These observations, together with the reduction of clonogenic potential early during adaptation, are consistent with a two-phase model for drug resistance. Initially, the rapid expansion of genetic diversity is counterbalanced by an intrinsic fitness penalty. Subsequently, normalization of SIM and fixation of stably resistant genomic configurations establish a new adaptive equilibrium.
Collectively, these data reveal conserved programs of mutagenesis as prominent contributors to therapeutic failure and provide a rational framework for synthetic lethal combinations of cytostatic agents with genotoxic therapies. Such combinations could potentially generate a lethal mutational load during the initial phase of adaptive evolution, thereby reducing therapeutic failure.
