Loss of PTEN in triple-negative breast cancer cell lines significantly correlates with AZD8186 sensitivity

Ocosu-Brackett et al.’S Figure 6 “Effect of the combination of AZD8186 and anti-PD1 on isogenic models” is featured on the cover of “Oncotarget” issue 11.

In vitro cell viability assays and immunoblots showed that loss of PTEN in triple-negative breast cancer cell lines was significantly associated with AZD8186 sensitivity.

AZD8186 combined with paclitaxel and eribulin has a synergistic effect on the growth inhibition of PTEN-losing cells.

AZD8186 significantly enhanced the antitumor efficacy of anti-PD1 antibodies in a melanoma xenograft model of PTEN-deficient BP mice, but not in a PTEN wild-type CT26 xenograft model.

In vitro, cell proliferation and colony formation assays were performed to determine the sensitivity of the cells to AZD8186.

AZD8186 has single-agent efficacy in TNBC cell lines lacking PTEN, but has limited single-agent efficacy in vivo.

“Phosphatidylinositol,” said the University of Texas Medical Anderson Cancer Center’s Department of Surgical Oncology, the Department of Research Cancer Therapy, the Department of Breast Cancer Surgery, and the Dr. Franka Meric-Bernstam Research Center in Houston, Texas, USA The 3-kinase (PI3K) / AKT / mTOR pathway is an important regulator of many physiological cellular processes that promote normal cell differentiation, proliferation, and survival. ”

The phosphatidylinositol 3-kinase (PI3K) / AKT / mTOR pathway is an important regulator of many physiological cell processes that promote normal cell differentiation, proliferation, and survival.

——Dr. Funda Meric-Bernstam, Department of Cancer Therapy, Department of Breast Surgery, Oncology and Sheikh Khalifa Bin Zayed Al Nahyan Personalized Cancer Therapy Institute

MiRNA mutation, loss of copy number, epigenetic silencing, and downregulation of PTEN protein can lead to inactivation of PTEN function, leading to activation of the PI3K / AKT / mTOR pathway, which in turn increases tumor growth in a variety of solids, invades and metastases tumors including the breast Cancer, endometrial cancer, prostate cancer, renal cell carcinoma, hepatocellular carcinoma, glioblastoma and colorectal cancer.

Loss of PTEN and increased PI3K signaling are related to the resistance of hormone receptor-positive breast cancer to trastuzumab and endocrine therapy, and the poor prognosis of triple-negative breast cancer.

In vitro, they consumed PIK3CB, which encodes PI3K, to reveal the significant growth inhibitory effect of PTEN-deficient tumors, whereas in corresponding PTEN-deficient tumors, to inhibit PIK3CA or encodes PI3K respectively. For PI3K, it did not have this growth inhibitory effect.

Therefore, the PI3K subtype is a driver of abnormal proliferation in PTEN-deficient cancers, and therefore, PI3K is a promising target for the treatment of PTEN-deficient TNBC. AZD8186 is a selective and potent small molecule inhibitor of PI3K with additional activity on PI3K isoforms.

The Merrick-Bernstam research team concluded in their Oncotarget paper, “These results provide preclinical evidence for the antitumor efficacy of AZD8186 in PTEN-deficient solid tumors. AZD8186 has a single drug in TNBC cell lines lacking PTEN Efficacy, with a modest single-agent effect in the body. In addition, AZD8186 enhances the antitumor effect of paclitaxel, but the use of this combination in an immunosuppressive model can observe stable and progressive disease. In an immune-capable model, AZD8186 Combination with anti-PD1 can lead to regression of PTEN-deficient BP tumors. We realize that although AZD8186 sensitivity is associated with PTEN loss, we can only speculate on causality. In conclusion, although further understanding of the mechanism of action of these combinations is required. ”

 

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