GATA2–IGF2 Mediates Chemotherapy Resistance in Lethal Prostate Cancer

Although patients with disseminated castration-resistant prostate cancer (CRPC) initially respond to treatment with taxane chemotherapy such as docetaxel, progression to lethal chemotherapy-resistant tumors often occurs. However, the mechanisms underlying chemotherapy resistance remain poorly understood. Vidal and colleagues found that GATA2, a transcription factor that regulates androgen receptor (AR) transcriptional activity, was upregulated in both docetaxel-resistant CRPC cell lines and during progression to disseminated chemotherapy-resistant disease in human prostate cancer. Depletion of GATA2 in chemotherapy-resistant CRPC cells and patient-derived xenograft models resulted in increased sensitivity to taxanes, induction of apoptosis, and diminished tumorigenicity in vivo, implicating GATA2 as a determinant of aggressiveness in CRPC. Transcriptional profiling of chemotherapy-resistant CRPC cells identified a signature of 28 GATA2-regulated genes that was enriched in patients with lethal prostate cancer and was independent of AR. In particular, GATA2 directly induced the expression of insulin-like growth factor 2 (IGF2), which was upregulated during disease progression and in patients treated with taxane chemotherapy and was required for GATA2-mediated chemotherapy resistance and tumorigenicity. Depletion of IGF2 resulted in reduced taxane resistance and tumor growth, whereas the addition of recombinant IGF2 was sufficient to rescue the effects of GATA2 depletion in chemotherapy-resistant cells. Mechanistically, GATA2-driven IGF2 expression stimulated IGF1 receptor (IGF1R) and insulin receptor (INSR), resulting in activation of effector kinases, including PI3K–AKT and JNK; combined inhibition of these downstream pathways abrogated chemotherapy resistance and soft-agar growth. Importantly, treatment with a dual inhibitor of IGF1R/INSR restored sensitivity to taxane chemotherapy in xenograft models and improved overall survival in preclinical models of disseminated disease. These findings identify GATA2–IGF2 signaling as an important mediator of chemotherapy resistance and aggressiveness in lethal prostate cancer and suggest that IGF1R/INSR may be an effective therapeutic target.

Vidal SJ, Rodriguez-Bravo V, Quinn SA, Rodriguez-Barrueco R, Lujambio A, Williams E, et al. A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer. Cancer Cell 2015;27:223–39.

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