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Akt inhibition with MK-2206 is associated with favorable immune profile changes within the tumor microenvironment of hormone receptor positive, HER2 negative breast cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150512 | GEO | 2020/05/25

REPOSITORIES: GEO

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Akt inhibition with MK-2206 is associated with favorable immune profile changes within the tumor microenvironment of hormone receptor positive, HER2 negative breast cancer [PI3K panel]

Project description:Gene expression was assessed with Nanostring in the surgical specimens obtained from a Window of Opportunity trial with MK-2206 in early stage breast cancer. Tumor biopsies and surgical specimens were compared for patients who received MK-2206 along with a prospective untreated control group of patients. Greater expression of interferon related genes was seen in surgical specimens following MK-2206 and compared to untreated controls.

2020-05-25 | GSE150509 | GEO

Akt inhibition with MK-2206 is associated with favorable immune profile changes within the tumor microenvironment of hormone receptor positive, HER2 negative breast cancer [IO360 panel]

2020-05-25 | GSE150458 | GEO

Akt Inhibition Is Associated With Favorable Immune Profile Changes Within the Tumor Microenvironment of Hormone Receptor Positive, HER2 Negative Breast Cancer.

Project description:Background: The PI3K/Akt/mTOR pathway in part impacts tumorigenesis through modulation of host immune activity. To assess the effects of Akt inhibition on the tumor micro-environment (TME), we analyzed tumor tissue from patients with operable hormone receptor positive, HER2 negative breast cancer (BC) treated on a presurgical trial with the Akt inhibitor MK-2206. Methods: Quantitative multiplex immunofluorescence (qmIF) was performed using CD3, CD8, CD4, FOXP3, CD68, and pancytokeratin on biopsy and surgical specimens of MK-2206 and untreated, control patients. nanoString was performed on surgical specimens to assess mRNA expression from MK-2206-treated vs. control patients. Results: Increased CD3+CD8+ density was observed in post vs. pre-treatment tissue in the MK-2206-treated vs. control patients (87 vs. 0.2%, p < 0.05). MK-2206 was associated with greater expression of interferon signaling genes (e.g., IFI6, p < 0.05) and lower expression of myeloid genes (CD163, p < 0.05) on differential expression and gene set enrichment analyses. Greater expression of pro-apoptotic genes (e.g., BAD) were associated with MK-2206 treatment (p < 0.05). Conclusion: Akt inhibition in operable BC was associated with a favorable immune profile in the TME, including increased CD3+CD8+ density and greater expression of interferon genes. Additional studies are warranted, as this may provide rationale for combining Akt inhibition with immunotherapy.

| S-EPMC7308467 | biostudies-literature

Akt inhibition with MK-2206 is associated with favorable immune profile changes within the tumor microenvironment of hormone receptor positive, HER2 negative breast cancer

Project description:Akt inhibition with MK-2206 is associated with favorable immune profile changes within the tumor microenvironment of hormone receptor positive, HER2 negative breast cancer

| PRJNA632732 | ENA

Akt inhibition with MK-2206 is associated with favorable immune profile changes within the tumor microenvironment of hormone receptor positive, HER2 negative breast cancer [IO360 panel]

Project description:Akt inhibition with MK-2206 is associated with favorable immune profile changes within the tumor microenvironment of hormone receptor positive, HER2 negative breast cancer [IO360 panel]

| PRJNA632489 | ENA

Akt inhibition with MK-2206 is associated with favorable immune profile changes within the tumor microenvironment of hormone receptor positive, HER2 negative breast cancer [PI3K panel]

| PRJNA632733 | ENA

A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors.

Project description:Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling.Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule.A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206.Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation.ClinicalTrials.gov; identifier: NCT00963547.

| S-EPMC3979046 | biostudies-literature

A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III <i>PIK3CA</i>-Mutant ER-Positive and HER2-Negative Breast Cancer.

Project description:Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor-positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer.Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2- breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17.Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery.Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823-32. ©2017 AACR.

| S-EPMC6392430 | biostudies-literature

Immune microenvironment and intrinsic subtyping in hormone receptor-positive/HER2-negative breast cancer.

Project description:Little is known regarding the interaction between immune microenvironment and tumor biology in hormone receptor (HR)+/HER2- breast cancer (BC). We here assess pretreatment gene-expression data from 66 HR+/HER2- early BCs from the LETLOB trial and show that non-luminal tumors (HER2-enriched, Basal-like) present higher tumor-infiltrating lymphocyte levels than luminal tumors. Moreover, significant differences in immune infiltrate composition, assessed by CIBERSORT, were observed: non-luminal tumors showed a more proinflammatory antitumor immune infiltrate composition than luminal ones.

| S-EPMC7881184 | biostudies-literature

Biomarkers of response to Akt inhibitor MK-2206 in breast cancer.

Project description:We tested the hypothesis that allosteric Akt inhibitor MK-2206 inhibits tumor growth, and that PTEN/PIK3CA mutations confer MK-2206 sensitivity.MK-2206 effects on cell signaling were assessed in vitro and in vivo. Its antitumor efficacy was assessed in vitro in a panel of cancer cell lines with differing PIK3CA and PTEN status. Its in vivo efficacy was tested as a single agent and in combination with paclitaxel.MK-2206 inhibited Akt signaling and cell-cycle progression, and increased apoptosis in a dose-dependent manner in breast cancer cell lines. Cell lines with PTEN or PIK3CA mutations were significantly more sensitive to MK-2206; however, several lines with PTEN/PIK3CA mutations were MK-2206 resistant. siRNA knockdown of PTEN in breast cancer cells increased Akt phosphorylation concordant with increased MK-2206 sensitivity. Stable transfection of PIK3CA E545K or H1047R mutant plasmids into normal-like MCF10A breast cells enhanced MK-2206 sensitivity. Cell lines that were less sensitive to MK-2206 had lower ratios of Akt1/Akt2 and had less growth inhibition with Akt siRNA knockdown. In PTEN-mutant ZR75-1 breast cancer xenografts, MK-2206 treatment inhibited Akt signaling, cell proliferation, and tumor growth. In vitro, MK-2206 showed a synergistic interaction with paclitaxel in MK-2206-sensitive cell lines, and this combination had significantly greater antitumor efficacy than either agent alone in vivo.MK-2206 has antitumor activity alone and in combination with chemotherapy. This activity may be greater in tumors with PTEN loss or PIK3CA mutation, providing a strategy for patient enrichment in clinical trials.

| S-EPMC3772348 | biostudies-literature

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