Activation of PI3K Signaling in Merkel Cell Carcinoma

Abstract

Purpose Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor, often metastatic at presentation, for which current chemotherapeutic regimens are largely ineffective. As its pathogenesis is still unknown, we hypothesized that deregulation of signaling pathways commonly activated in cancer may contribute to MCC tumorigenesis and may provide insights into targeted therapy approaches for this malignancy. Experimental Design We retrospectively profiled 60 primary MCC samples using a SNaPshot-based tumor genotyping assay to screen for common mutations in 13 cancer genes. Results We identified mutations in 9 (15%) MCC primary tumors, including mutations in TP53 (3/60) and activating mutations in the PIK3CA gene (6/60). Sanger sequencing of the primary MCC tumors detected one additional PIK3CA mutation (R19K) that had not been previously described in cancer. Merkel cell polyoma virus (MCPyV) was detected in 38 (66%) MCC cases and patients with MCPyV-positive cancers showed a trend toward better survival. With one exception, the presence of MCPyV and of activating mutations in PIK3CA appeared mutually exclusive. We observed that signaling through the PI3K/pAKT pathway was active in one MCPyV-positive and in all MCPyV-negative MCC cell lines, as evidenced by AKT phosphorylation. Importantly, the presence of a PIK3CA activating mutation was associated with sensitivity to treatment with ZST474, a specific PI3K inhibitor and to NVP-BEZ235, a dual PI3K-mTOR inhibitor, targeted agents under active clinical development. Conclusions PI3K pathway activation may drive tumorigenesis in a subset of MCC and screening these tumors for PIK3CA mutations could help identify patients who may respond to treatment with PI3K pathway inhibitors.

Effect of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against human Merkel cell carcinoma MKL-1 cells

“…confirmed the activation of PI3K/Akt/mTOR signaling in MCC, which was consistent with previous results (8). Consequently, it is reasonable to assume that targeting PI3K/Akt/mTOR may effectively contribute to the treatment of MCC through the hyperactivation of PI3K/Akt/mTOR signaling.…”

“…Components of the PI3K/Akt/mTOR pathway are frequently abnormal in a variety of tumors, making them an attractive target for anti-cancer therapy. Previously, Akt hyperphosphorylation has been found in MCV-independent MCC (7,8). In addition, chronic mTOR activation has been found to promote cell survival in MCC (9).…”

Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

“…These genes include PIK3-CA, TP53, and PTEN. [40][41][42][43] In our study cases, PIK3CA and TP53, but not PTEN, were found to harbor mutations, but only in small number of cases (Table 5). Using the gene level recurrence as a metric, we identified the retinoblastoma pathway as critical to Merkel cell carcinoma pathogenesis.…”

Cytokeratin 20-negative Merkel cell carcinoma is infrequently associated with the Merkel cell polyomavirus

“…12,23,25,[33][34][35][36] Recent findings indicate that Merkel cell polyomavirusnegative tumors may be associated with RB1 inactivating mutations 37 and (in a subset) PIK3CA activating mutations. 38 Hence, although additional study is needed to clarify differences between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative tumors, current data suggest that molecular differences exist that may have implications for immune-based or targeted therapy.…”