Senescence after growth arrest: a physiological mechanism by which CDK4/6 inhibitors can exert their anti-tumor effects

Organizers: IRB Barcelona
Date: Thursday 8 March 2018, 12.00h
Place: Aula Fèlix Serratosa, Parc Científic de Barcelona, Spain

Host: Dr. Manuel Serrano, IRB Barcelona

Abstract

Forty-five years ago the war on cancer was declared with the hope that an understanding of the genetics and biochemistry of the mammalian cell cycle would result in novel therapies that could control this insidious disease. This promise has been achieved at multiple levels with drugs that target various aspects of the cell cycle machinery. One class of compounds, those with high selectivity to the CDK4 and CDK6 kinases that control entry and exit from the cell cycle, have proven to have efficacy alone or in combination with a variety of other drugs to control progression of an array of different tumor types. While trying to understand the mechanism of action by which these drugs extend progression free survival in a subset of patients with well differentiated and dedifferentiated liposarcoma we uncovered a novel biological transition: senescence after growth arrest, or geroconversion. In this talk I will discuss recently published and submitted work describing how we identified this transition and the roles that MDM2, CDH18 and PDLIM7, as well as ATRX and HRAS play during it. In addition, I will present unpublished data describing the development of a system that allows us to follow the progression of cells synchronously through this transition, and how it helped us to identify elements of the senescence associated secretory program that drive cells specifically through the transition from reversible to irreversible growth arrest. Some of the gene products regulating the transition to irreversibility may also have conserved function during other types of cellular senescence.

Ohncology Programme Seminar