Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer

Jian Hu, Soyoon Sarah Hwang, Marc Liesa, Boyi Gan, Ergun Sahin, Mariela Jaskelioff, Zhihu Ding, Haoqiang Ying, Adam T. Boutin, Hailei Zhang, Shawn Johnson, Elena Ivanova, Maria Kost-Alimova, Alexei Protopopov, Yaoqi Alan Wang, Orian S. Shirihai, Lynda Chin, Ronald A. DePinho

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-1β, a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1β 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.

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