Functional Genetic Approach Identifies MET, HER3, IGF1R, INSR Pathways as Determinants of Lapatinib Unresponsiveness in HER2-Positive Gastric Cancer

Zhang, Zhe; Wang, Jiping; Ji, Dongmei; Wang, Chenchen; Liu, Rujiao; Wu, Zheng; Liu, Lian; Zhu, Dan; Chang, Jinjia; Geng, Ruixuan; Xiong, Lei; Fang, Qiangyi; Li, Jin

doi:10.1158/1078-0432.ccr-13-3396

Cited by 62 publications

(73 citation statements)

References 35 publications

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“…However, some reports have shown that loss of PTEN expression or deletion of the PTEN gene is rarely found (3.7-5.3 %) in HER2-overexpressing gastric cancer [23,24]. The discrepancy in these results might be due to variations in the definition of PTEN loss.…”

Section: Discussionmentioning

confidence: 96%

PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma

et al. 2016

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Background Although trastuzumab improves the outcome of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric or gastroesophageal junction adenocarcinoma (collectively referred to as ''gastroesophageal adenocarcinoma''; GEA), no clinical response is observed in a substantial population of patients. A predictive biomarker of trastuzumab response is required. The aim of this study was to evaluate whether the hyperactivation of the downstream phosphatidylinositol 3-kinase pathway, due to phosphatase and tensin homolog (PTEN) loss or PIK3CA mutations, could provide trastuzumab resistance in GEA. Methods Expression of HER2 and PTEN, and PIK3CA gene mutations were screened in 264 surgically resected GEA specimens. The effects of PTEN knockdown on the response to trastuzumab on cell viability, HER2 downstream signaling, apoptosis, and cell cycle were evaluated in HER2-overexpressing NCI-N87 gastric adenocarcinoma and OE19 esophageal adenocarcinoma cell lines. Inhibition of xenograft tumor growth by trastuzumab was investigated in OE19 cells with or without PTEN knockdown. The PTEN expression and objective response were analyzed in 23 GEA patients who received trastuzumab-based therapy.Results PTEN loss was identified in 34.5 % of HER2-overexpressing GEA patients, whereas PIK3CA mutations were rare (5.6 %). Trastuzumab-mediated growth suppression, apoptosis, and G 1 cell cycle arrest were inhibited by PTEN knockdown through Akt activation in NCI-N87 and OE19 cells. PTEN knockdown impaired the antiproliferative effect of trastuzumab in OE19 xenograft models. A clinical response was observed in 50 % of PTEN-positive tumors (9 of 18) but in no tumors with PTEN loss (none of 5). Conclusions PTEN loss was frequently found in HER2-overexpressing tumors, and was associated with a poor response to trastuzumab-based therapy in patients with GEA.

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Section: Discussionmentioning

confidence: 96%

PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma

et al. 2016

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“…S3A). Next, a Cre-inducible allele of the MET receptor tyrosine kinase, which is associated with EMT and therapy resistance (18,19), and expressed at high levels in breast cancer (20)(21)(22), was introduced in KB1P-Col1a1 ESC clone A2.1 to produce K14cre;Brca1 F/F ; Trp53 F/F ;Col1a1 inv-CAG-Met-Luc (KB1P-MET) ESCs (Fig. S3B).…”

Section: Met Accelerates Mammary Tumor Development In Kb1p Chimericmentioning

confidence: 99%

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Henneman

Miltenburg

Michalak

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

108

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Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics. resistance | mouse model | breast cancer | BRCA1 | PARP P oly(ADP-ribose) polymerase (PARP) inhibition provides a promising therapeutic strategy for targeting homologous recombination (HR)-deficient tumors, such as breast cancer 1 (BRCA1)-mutated cancers (1). Indeed, clinical phase I and phase II trials have shown potent anticancer activity of small molecule inhibitors of PARP, such as olaparib, in patients with BRCA1-associated breast cancer (2, 3). However, it remains to be established whether different breast cancer subtypes in BRCA1 mutation carriers respond equally to PARP inhibition. Reduced sensitivity of breast cancers to anticancer drugs has frequently been associated with an epithelial-to-mesenchymal transition (EMT) (4-7). Metaplastic breast carcinomas (MBCs) are a subset of triple-negative breast cancers (TNBCs) characterized by a claudin-low and EMT-like phenotype (8) and a poor prognosis compared with other TNBCs (9). More than 60% of MBCs have BRCA1 promoter methylation, raising the question whether these tumors can be effectively targeted by using PARP inhibitors (10). To address this issue in an experimentally controlled setting, we set out to generate a genetically engineered mouse model (GEMM) of BRCA1-deficient MBC by inducing EMT via MET overexpression in a previously established GEMM of BRCA1-mutated breast cancer. We report that EMT is associated with olaparib resistance and can be effectively bypassed by administration of AZD2461, a PARP inhibitor with low affinity for the P-glycoprotein (Pgp) drug efflux transporter. Results Development of a GEMM-ESC Strategy for Mouse Mammary TumorModels. GEMMs have the potential to capture the cell-intrinsic and cell-extrinsic factors that drive de novo tumor formation, making them exceptionally valuable for cancer research (11). To speed up the development of novel multiallele GEMMs of human cancer, we...

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“…IGF1R has been suggested to play a role in ovarian cancer due to its upregulation after combined PI3K and mTOR inhibition (43) as well as in a range of ovarian cancer cell lines after AKT inhibition (20), but was not pursued with functional inhibitor experiments in these studies. These and other (44)(45)(46)(47) examples demonstrate that IGF1R inhibition may prove a valuable addition to inhibitors targeting the MAPK and PI3K pathways.…”

Section: Discussionmentioning

confidence: 88%

Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R

Lint

Poell

Soueidan

et al. 2016

Molecular Cancer Therapeutics

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Targeted therapies have proven invaluable in the treatment of breast cancer, as exemplified by tamoxifen treatment for hormone receptor-positive tumors and trastuzumab treatment for HER2-positive tumors. In contrast, a subset of breast cancer negative for these markers, triple-negative breast cancer (TNBC), has met limited success with pathway-targeted therapies. A large fraction of TNBCs depend on the PI3K pathway for proliferation and survival, but inhibition of PI3K alone generally has limited clinical benefit. We performed an RNAibased genetic screen in a human TNBC cell line to identify kinases whose knockdown synergizes with the PI3K inhibitor GDC-0941 (pictilisib). We discovered that knockdown of insulin-like growth factor-1 receptor (IGF1R) expression potently increased sensitivity of these cells to GDC-0941. Pharmacologic inhibition of IGF1R using OSI-906 (linsitinib) showed a strong synergy with PI3K inhibition. Furthermore, we found that the combination of GDC-0941 and OSI-906 is synergistic in 8 lines from a panel of 18 TNBC cell lines. In these cell lines, inhibition of IGF1R further decreases the activity of downstream PI3K pathway components when PI3K is inhibited. Expression analysis of the panel of TNBC cell lines indicates that the expression levels of IGF2BP3 can be used as a potential predictor for sensitivity to the PI3K/IGF1R inhibitor combination. Our data show that combination therapy consisting of PI3K and IGF1R inhibitors could be beneficial in a subset of TNBCs. Mol Cancer Ther; 15(7); 1545-56. Ó2016 AACR.

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Functional Genetic Approach Identifies MET, HER3, IGF1R, INSR Pathways as Determinants of Lapatinib Unresponsiveness in HER2-Positive Gastric Cancer

Cited by 62 publications

References 35 publications

PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma

PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R

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