Involvement of NEDD9 and HSP90 in signaling and therapeutic response in cancer and ADPKD

Meghan C. Kopp

doi:10.17918/00007385

As more chemotherapeutics are developed and judged safe for use in humans, they can also be exploited for other uses beyond treatment of cancer. By exploring the altered signaling pathways in various diseases, we can find potential new therapies for common as well as rare or untreatable diseases (without the need for developing new drugs). Autosomal Dominant Polycystic Kidney Disease (ADPKD or PKD) has no current therapeutic preventatives or cures, although it affects one in every 500 to 1000 individuals, making the prevalence in the US alone about 600,000 PKD patients, who inherit mutations in the PKD1 or PKD2 genes. As PKD signaling becomes better understood, a number of signaling cascades important to the pathogenesis of this disease have been found to mirror cancer signaling, suggesting there could be therapeutic benefit in treating ADPKD patients with chemotherapeutics. My work has focused on elucidating the function of two signaling scaffolds in cancer and PKD, with the goal of improving therapeutic options for these diseases. NEDD9 and HSP90 are important signaling hubs that are frequently upregulated in cancer. NEDD9 helps relay signals from integrins and growth factor receptors to downstream target kinases and signals for survival, metastasis, and possibly DNA damage signaling. HSP90 is a signaling chaperone protein that helps to stabilize and refold many misfolded proteins: in cancer, HSP90 can also stabilize oncogenic mutants to drive disease progression, including NEDD9 signaling partners such as AURKA and SRC. Our group has investigated the function of NEDD9, AURKA, and HSP90 in cancer and cystogenesis in PKD. Previous work showed that NEDD9 and AURKA played roles in limiting cyst formation. In my studies, I found that alisertib, an AURKA inhibitor, promoted cyst growth, suggesting it should be avoided in cancer therapies for patients with PKD. In contrast, I found that treatment with erlotinib, an EGFR inhibitor, reduced cyst burden in PKD1 null mice, and treatment with a metabolic regulator, 2DG, and the HSP90 inhibitor ganetespib help to delay cystogenesis in PKD1 null mice. In cancer, I found that NEDD9 knockout mice crossed to an inducible KRAS/p53 model for lung cancer showed a significant increase in tumor burden compared to NEDD9 wt/KRAS/p53 mice. Tumors lacking NEDD9 also showed an increased therapeutic response to dasatinib, a SRC and BCR/Abl inhibitor, but not the HSP90 inhibitor ganetespib, or a combination of the two drugs. In further studies of NEDD9, knockdown of this gene in SCC61 head and neck cancer and A549 lung cancer cells reduced cell survival under drug induced cytotoxic/nuclear stress, based on IC50 curves. Strikingly, we also found that NEDD9 KD had opposing effects on SCC61 cells and A549 cells in [gamma]-H2AX foci formation and colony formation assays. NEDD9 was found for the first time to have an effect on the DNA damage response, sensitizing A549 cells to cytotoxic agents but increasing DNA repair and cell survival in SCC61 cells. We also performed the first evaluation of STA-8666, an HSP90-targeted cytotoxic agent, on Small Cell Lung Cancer (SCLC) models. This drug was highly effective against xenograft SCLC tumors, and proved curative in most mice without inducing cachexia, which often limits standard therapies from being used at effective doses. From this work, we conclude that NEDD9 and HSP90 are both important modulators of the therapeutic response for cancer and PKD, and targeting these genes and related signaling may offer new treatments.

Involvement of NEDD9 and HSP90 in signaling and therapeutic response in cancer and ADPKD

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Involvement of NEDD9 and HSP90 in signaling and therapeutic response in cancer and ADPKD

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