A Targetable GATA2-IGF2 Axis Confers Aggressiveness in Lethal Prostate Cancer

• GATA2 regulates chemotherapy resistance and tumorigenicity in lethal prostate cancer
• GATA2 regulates a signature of cancer-progression-associated genes that includes IGF2
• IGF2 significantly mediates the aggressive properties regulated by GATA2
• IGF1R/INSR inhibition restores the efficacy of chemotherapy and improves survival

SummaryElucidating the determinants of aggressiveness in lethal prostate cancer may stimulate therapeutic strategies that improve clinical outcomes. We used experimental models and clinical databases to identify GATA2 as a regulator of chemotherapy resistance and tumorigenicity in this context. Mechanistically, direct upregulation of the growth hormone IGF2 emerged as a mediator of the aggressive properties regulated by GATA2. IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program. The characterization of this axis prompted a combination strategy whereby dual IGF1R/INSR inhibition restored the efficacy of chemotherapy and improved survival in preclinical models. These studies reveal a GATA2-IGF2 aggressiveness axis in lethal prostate cancer and identify a therapeutic opportunity in this challenging disease.

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