A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer

Berns, Katrien; Horlings, Hugo M.; Hennessy, Bryan T.; Madiredjo, Mandy; Hijmans, E. Marielle; Beelen, Karin; Linn, Sabine C.; González-Angulo, Ana M.; Stemke-Hale, Katherine; Hauptmann, Michael; Beijersbergen, Roderick L.; Mills, Gordon B.; Vijver, Marc J. van de; Bernards, René

doi:10.1016/j.ccr.2007.08.030

Cited by 1,417 publications

(1,123 citation statements)

References 19 publications

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“…Likewise, breast cancers with either activating mutations in PIK3CA or with loss of PTEN expression respond poorly to treatment with the Her2/Neu targeting antibody, trastuzumab. 52 Consistent with the present findings, Frattini et al recently reported that colon tumors with loss of PTEN expression have significantly reduced response to cetuximab. 48 Furthermore, PIK3CA mutations and PTEN loss in colorectal tumors are statistically and significantly associated with lack of response to panitumumab or cetuximab treatment.…”

Section: Pten-pi3k-akt-mtor Pathway Alterationssupporting

confidence: 93%

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Rizzo

Bronte

Fanale

et al. 2010

Cancer Treatment Reviews

102

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s u m m a r yAn important molecular target for metastatic CRC treatment is the epidermal growth factor receptor (EGFR). Many potential biomarkers predictive of response to anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have been retrospectively evaluated, including EGFR activation markers and EGFR ligands activation markers. With regard to the "negative predictive factors" responsible for primary or intrinsic resistance to anti-EGFR antibodies a lot of data are now available. Among these, KRAS mutations have emerged as a major predictor of resistance to panitumumab or cetuximab in the clinical setting and several studies of patients receiving first and subsequent lines of treatment have shown that those with tumors carrying KRAS mutations do not respond to EGFR-targeted monoclonal antibodies or show any survival benefit from such treatments. The role of B-RAF mutations, mutually exclusive with KRAS mutations, in predicting resistance to anti-EGFR mAbs is not yet consolidated. It therefore appears that BRAF mutations may play a strong negative prognostic role and only a slight role in resistance to anti-EGFR Abs.

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Section: Pten-pi3k-akt-mtor Pathway Alterationssupporting

confidence: 93%

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Rizzo

Bronte

Fanale

et al. 2010

Cancer Treatment Reviews

102

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“…Thus, intrinsic resistance of HER2-amplified Luminal mRNA tumors to trastuzumab-based chemotherapy regimens may exist. Reported mechanisms of resistance to trastuzumab include altered receptor-antibody interaction, signaling by HER receptor family members, IGF1R signaling, modulation of P27 KIP1 and loss of PTEN and/or PI3K pathway activation [40,41]. We observed that the PTEN mRNA expression in the HER2?…”

Section: Discussionmentioning

confidence: 69%

Concordance of clinical and molecular breast cancer subtyping in the context of preoperative chemotherapy response

Ronde

Hannemann

Halfwerk

et al. 2009

Breast Cancer Res Treat

146

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“…Although these inhibitors have revolutionized the treatment of GIST and other malignancies, management of intrinsic and acquired resistance mechanisms remain a clinical challenge. Activation of the PI3K/AKT pathway, downstream of activated RTKs, has been shown to both predict and promote resistance to RTK inhibitors in GIST and in other malignancies (7,9,10,39-41). Clinical trials are currently underway to investigate the use of PI3K/AKT inhibitors in combination with RTK inhibitors in CLL, melanoma, and NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Zook

Pathak

Belinsky

et al. 2017

Clinical Cancer Research

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Purpose Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate (IM) or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3-kinase/AKT pathway in the survival of IM-resistant GIST cell lines and tumors. Experimental Design Here, we performed in vitro and in vivo studies evaluating the novel combination of IM with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST. Results This drug combination demonstrated significant synergistic effects in a panel of IM-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in IM-sensitive GIST xenografts as compared to treatment with IM or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 (BEX1) and neuronal pentraxin I (NPTX1), whose expression was significantly up-regulated in combination-treated tumors compared to tumors treated with the two monotherapies. Conclusion These studies provide strong preclinical justification for combining IM with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect.

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A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer

Cited by 1,417 publications

References 19 publications

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Concordance of clinical and molecular breast cancer subtyping in the context of preoperative chemotherapy response

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

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