Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer
Menée sur des modèles murins de lymphome et de cancer de la prostate, ces deux études évaluent les effets de l'inhibition de la télomérase sur la croissance tumorale
To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in T cell lymphomas arising in Atm / mice engineered with an inducible telomerase reverse transcriptase allele. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with alleviation of telomere dysfunction-induced checkpoints. These cancers possessed copy number alterations targeting key loci in human T cell lymphomagenesis. Upon telomerase extinction, tumor growth eventually slowed with reinstatement of telomere dysfunction-induced checkpoints, yet growth subsequently resumed as tumors acquired alternative lengthening of telomeres (ALT) and aberrant transcriptional networks centering on mitochondrial biology and oxidative defense. ALT+ tumors acquired amplification/overexpression of PGC-1², a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1² or SOD2 knockdown. Genetic modeling of telomerase extinction reveals vulnerabilities that motivate coincidental inhibition of mitochondrial maintenance and oxidative defense mechanisms to enhance antitelomerase cancer therapy. º Telomerase reactivation following genomic instability promotes invasiveness º Telomerase inhibition leads to cell death and eventual ALT-dependent resistance º ALT+ cells upregulate PGC axis to rescue mitochondrial dysfunction and reactive oxygen species (ROS) º Mitochondria/ROS fitness can be targeted to enhance antitelomerase therapy Decreasing telomerase activity initially slows tumor growth in a mouse model of lymphoma, but eventually growth resumes as resistant cells emerge. These cells display aberrant mitochondrial function and are sensitive to PGC-1² inhibition, offering a new target for enhancing the effectiveness of antitelomerase therapy.