Caveolin-1 Dependent Endocytosis Enhances the Chemosensitivity of HER-2 Positive Breast Cancer Cells to Trastuzumab Emtansine (T-DM1)

Chung, Yuan‐Chiang; Kuo, Jang-Fang; Wei, Wan‐Chen; Chang, King‐Jen; Chao, Wei‐Ting

doi:10.1371/journal.pone.0133072

Cited by 43 publications

(50 citation statements)

References 56 publications

(70 reference statements)

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“…Unlike MMAF, monomethyl auristatin E (MMAE) does not exist as a charged molecule at neutral pH and is membrane permeable. Data herein implicate caveolae-mediated endocytosis in T-DM1 resistance; however, another group has suggested that caveolae-mediated endocytosis may sensitize cells to T-DM1 (33). Although these data implicate a possible role for CAV1, the inherent differences in sensitivity to free DM1 (18) may explain the differences in basal sensitivity to T-DM1 seen across the high HER2 cell lines evaluated in that study.…”

Section: Discussionmentioning

confidence: 53%

Caveolae-Mediated Endocytosis as a Novel Mechanism of Resistance to Trastuzumab Emtansine (T-DM1)

Sung

Tan

et al. 2018

Molecular Cancer Therapeutics

139

111

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Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2þ metastatic breast cancer; however, its clinical activity is limited by inherent or acquired drug resistance. The molecular mechanisms that drive clinical resistance to T-DM1, especially in HER2 þ tumors, are not well understood. We used HER2 þ cell lines to develop models of T-DM1 resistance using a cyclical dosing schema in which cells received T-DM1 in an "onoff" routine until a T-DM1-resistant population was generated. T-DM1-resistant N87 cells (N87-TM) were cross-resistant to a panel of trastuzumab-ADCs (T-ADCs) with non-cleavablelinked auristatins. N87-TM cells do not have a decrease in HER2 protein levels or an increase in drug transporter protein (e.g., MDR1) expression compared with parental N87 cells.

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Section: Discussionmentioning

confidence: 53%

Caveolae-Mediated Endocytosis as a Novel Mechanism of Resistance to Trastuzumab Emtansine (T-DM1)

Sung

Tan

et al. 2018

Molecular Cancer Therapeutics

139

111

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“…5A). Since it has been reported that Her2 can be taken up via caveolin-1 dependent endocytosis and, to a lesser extent, clathrin-mediated endocytosis, [59][60][61][62] this difference likely represents anti-Her2-scFv-exosomes binding to Her2 and concomitant internalisation with the receptor. Thus, by directing exosomes to bind to a specific cell surface receptor, we have shown that it is possible to alter the trafficking and likely intracellular fate of the cargo.…”

Section: Discussionmentioning

confidence: 99%

High affinity single-chain variable fragments are specific and versatile targeting motifs for extracellular vesicles

Longatti¹,

Schindler²,

Collinson³

et al. 2018

Nanoscale

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Exosomes are extracellular vesicles that mediate cell-to-cell communication by transferring biological cargo, such as DNA, RNA and proteins. Through genetic engineering of exosome-producing cells or manipulation of purified exosomes, it is possible to load exosomes with therapeutic molecules and target them to specific cells via the display of targeting moieties on their surface. This provides an opportunity to exploit a naturally-occurring biological process for therapeutic purposes. In this study, we explored the potential of single chain variable fragments (scFv) as targeting domains to achieve delivery of exosomes to cells expressing a cognate antigen. We generated exosomes targeting the Her2 receptor and, by varying the affinity of the scFvs and the Her2 expression level on recipient cells, we determined that both a high-affinity anti-Her2-scFv (K≤ 1 nM) and cells expressing a high level (≥10 copies per cell) of Her2 were optimally required to enable selective uptake. We also demonstrate that targeting exosomes to cells via a specific cell surface receptor can alter their intracellular trafficking route, providing opportunities to influence the efficiency of delivery and fate of intracellular cargo. These experiments provide solid data to support the wider application of exosomes displaying antibody fragments as vehicles for the targeted delivery of therapeutic molecules.

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“…It is believed that the HER2/T-DM1 conjugate enters cancer cells via the clathrin-dependent endocytosis pathway. However, a clathrin-independent mechanism, such as caveolae membranes composed mainly by caveolin-1 has also been demonstrated (22). Furthermore, it has been shown that the high endocytic activity of stem cell-like breast cancer cells make them particularly sensitive to T-DM1 (23).…”

Section: Discussionmentioning

confidence: 99%

Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer

Sabbaghi

Gil‐Gómez

Guardia

et al. 2017

Clinical Cancer Research

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Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance. HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3, and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions. Genetic modifications to up- or downregulate were conducted. Effects of T-DM1 on cyclin B1 levels, proliferation, and apoptosis were assayed in human-positive breast cancer explants. We obtained three cell lines with different levels of acquired T-DM1 resistance (HCC1954/TDR, HCC1419/TDR, and SKBR3/TDR cells). HER2 remained amplified in the resistant cells. Binding to HER2 and intracellular uptake of T-DM1 were maintained in resistant cells. T-DM1 induced cyclin B1 accumulation in sensitive but not resistant cells. knockdown by siRNA in parental cells induced T-DM1 resistance, while increased levels of cyclin B1 by silencing partially sensitized resistant cells. In a series of 18 HER2-positive breast cancer fresh explants, T-DM1 effects on proliferation and apoptosis paralleled cyclin B1 accumulation. Defective cyclin B1 induction by T-DM1 mediates acquired resistance in HER2-positive breast cancer cells. These results support the testing of cyclin B1 induction upon T-DM1 treatment as a pharmacodynamic predictor in HER2-positive breast cancer. .

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Caveolin-1 Dependent Endocytosis Enhances the Chemosensitivity of HER-2 Positive Breast Cancer Cells to Trastuzumab Emtansine (T-DM1)

Cited by 43 publications

References 56 publications

Caveolae-Mediated Endocytosis as a Novel Mechanism of Resistance to Trastuzumab Emtansine (T-DM1)

Caveolae-Mediated Endocytosis as a Novel Mechanism of Resistance to Trastuzumab Emtansine (T-DM1)

High affinity single-chain variable fragments are specific and versatile targeting motifs for extracellular vesicles

Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer

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