Resistance to human epidermal growth factor receptor type 2-targeted therapies

Théry, Jean-Christophe; Spano, Jean‐Philippe; Azria, D.; Raymond, Éric; Llorca, F. Penault

doi:10.1016/j.ejca.2014.01.003

Cited by 47 publications

(39 citation statements)

References 80 publications

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“…2) 53, 54. Both of these alterations could explain the clinical failure of trastuzumab 55, 56, 57, 58, 59, 60. The Δ16HER‐2, a type of oncogenic variant caused by the in‐frame deletion of exon 16 in the extracellular domain of HER‐2, is reported to comprise 4–9% of total HER‐2 transcripts 56, 61.…”

Section: The Her‐2 Mutations and Variantsmentioning

confidence: 99%

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Sun

Shi

Shen

et al. 2015

J Cellular Molecular Medi

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Studies over the last two decades have identified that amplified human epidermal growth factor receptor (HER‐2; c‐erbB‐2, neu) and its overexpression have been frequently implicated in the carcinogenesis and prognosis in a variety of solid tumours, especially breast cancer. Lots of painstaking efforts were invested on the HER‐2 targeted agents, and significantly improved outcome and prolonged the survival of patients. However, some patients classified as ‘HER‐2‐positive’ would be still resistant to the anti‐HER‐2 therapy. Various mechanisms of drug resistance have been illustrated and the alteration of HER‐2 was considered as a crucial mechanism. However, systematic researches in regard to the HER‐2 mutations and variants are still inadequate. Notably, the alterations of HER‐2 play an important role in drug resistance, but also have a potential association with the cancer risk. In this review, we summarize the possible mutations and focus on HER‐2 variants’ role in breast cancer tumourigenesis. Additionally, the alteration of HER‐2, as a potential mechanism of resistance to trastuzumab, is discussed here. We hope that HER‐2 related activating mutations could potentially offer more therapeutic opportunities to a broader range of patients than previously classified as HER‐2 overexpressed.

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Section: The Her‐2 Mutations and Variantsmentioning

confidence: 99%

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Sun

Shi

Shen

et al. 2015

J Cellular Molecular Medi

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“…However, development of resistance to antibody therapies is widespread, and an understanding of the resistance mechanisms is a topic of great interest and clinical urgency (4)(5)(6)(7). In the case of breast cancer, it is well established that the humanized IgG1 antibody trastuzumab can inhibit tumor growth by binding via its variable domain to highly expressed HER2 receptors on cancer cells to inhibit cell signaling (4,(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

A Novel Therapeutic Strategy to Rescue the Immune Effector Function of Proteolytically Inactivated Cancer Therapeutic Antibodies

Fan

Brezski

Deng

et al. 2015

Molecular Cancer Therapeutics

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Primary and acquired resistance to anticancer antibody immunotherapies presents significant clinical challenges. Here, we demonstrate that proteolytic inactivation of cancer-targeting antibodies is an unappreciated contributor to cancer immune evasion, and the finding presents novel opportunities for therapeutic intervention. A single peptide bond cleavage in the IgG1 hinge impairs cancer cell killing due to structural derangement of the Fc region. Hinge-cleaved trastuzumab gradually accumulated on the surfaces of HER2-expressing cancer cell lines in vitro, and was greatly accelerated when the cells were engineered to express the potent bacterial IgG-degrading proteinase (IdeS). Similar to cancer-related matrix metalloproteinases (MMP), IdeS exposes a hinge neoepitope that we have developed an antibody, mAb2095-2, to specifically target the epitope. In in vitro studies, mAb2095-2 restored the lost antibody-dependent cell-mediated cytotoxicity functionality of cell-bound single-cleaved trastuzumab (scIgG-T). In vivo, mAb2095-2 rescued the impaired Fc-dependent tumor-suppressive activity of scIgG-T in a xenograft tumor model and restored the recruitment of immune effector cells into the tumor microenvironment. More importantly, an Fc-engineered proteinase-resistant version of mAb2095-2 rescued trastuzumab antitumor efficacy in a mouse tumor model with human cancer cells secreting IdeS, whereas trastuzumab alone showed significantly reduced antitumor activity in the same model. Consistently, an Fc-engineered proteinase-resistant version of trastuzumab also greatly improved antitumor efficacy in the xenograft tumor model. Taken together, these findings point to a novel cancer therapeutic strategy to rescue proteolytic damage of antibody effector function by an Fc-engineered mAb against the hinge neoepitope and to overcome cancer evasion of antibody immunity.

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“…Although these HER2-targeted therapies combined with chemotherapy have improved the outcome for women with HER2-positive metastatic BC, not all patients respond and many patients with HER2-positive BC develop resistance within a year (3). Pertuzumab combined with trastuzumab and docetaxel has improved patient survival compared with trastuzumab and docetaxel alone (4).…”

mentioning

confidence: 99%

Dual-Receptor–Targeted Radioimmunotherapy of Human Breast Cancer Xenografts in Athymic Mice Coexpressing HER2 and EGFR Using ¹⁷⁷Lu- or ¹¹¹In-Labeled Bispecific Radioimmunoconjugates

et al. 2015

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One mechanism of resistance to trastuzumab in human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) is increased epidermal growth factor receptor (EGFR) expression. We have developed 111 In-labeled bispecific radioimmunoconjugates (bsRICs) that bind HER2 and EGFR on BC cells by linking trastuzumab Fab fragments through a polyethylene glycol (PEG 24 ) spacer to epidermal growth factor (EGF). We hypothesized that tumors coexpressing HER2 and EGFR could be treated by dualreceptor-targeted radioimmunotherapy with these bsRICs labeled with the β-particle emitter 177 In-labeled trastuzumab Fab or EGF killed tumor cells that predominantly expressed HER2 or EGFR, respectively, whereas bsRICs were cytotoxic to cells that displayed either HER2 or EGFR or both receptors. bsRICs were more effective than monospecific agents. 177 Lu-DOTA-Fab-PEG 24 -EGF was more cytotoxic than 111 In-DTPAFab-PEG 24 -EGF. The tumor uptake of 177 Lu-DOTA-Fab-PEG 24 -EGF was 2-fold greater than 177 Lu-DOTA-trastuzumab Fab or 177 Lu-DOTA-EGF. The NOAEL for 177 Lu-DOTA-Fab-PEG 24 -EGF was 11.1 MBq (10 μg).Trastuzumab-sensitive MDA-MB-231/H2N and trastuzumab-resistant TrR1 tumors were growth-inhibited by 177 Lu-DOTA-Fab-PEG 24 -EGF or 111 In-DTPA-Fab-PEG 24 -EGF. Unlabeled immunoconjugates had no effect on tumor growth. 177 Lu-DOTA-Fab-PEG 24 -EGF inhibited tumor growth more effectively than 111 In-DTPA-Fab-PEG 24 -EGF because of a 9.3-fold-higher radiation-absorbed dose (55.0 vs. 5.9 Gy, respectively). Conclusion: These results are encouraging for further development of these bsRICs for dual-receptor-targeted radioimmunotherapy of BC coexpressing HER2 and EGFR, including trastuzumab-resistant tumors.

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Resistance to human epidermal growth factor receptor type 2-targeted therapies

Cited by 47 publications

References 80 publications

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

A Novel Therapeutic Strategy to Rescue the Immune Effector Function of Proteolytically Inactivated Cancer Therapeutic Antibodies

Dual-Receptor–Targeted Radioimmunotherapy of Human Breast Cancer Xenografts in Athymic Mice Coexpressing HER2 and EGFR Using ¹⁷⁷Lu- or ¹¹¹In-Labeled Bispecific Radioimmunoconjugates

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Resistance to human epidermal growth factor receptor type 2-targeted therapies

Cited by 47 publications

References 80 publications

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

A Novel Therapeutic Strategy to Rescue the Immune Effector Function of Proteolytically Inactivated Cancer Therapeutic Antibodies

Dual-Receptor–Targeted Radioimmunotherapy of Human Breast Cancer Xenografts in Athymic Mice Coexpressing HER2 and EGFR Using 177Lu- or 111In-Labeled Bispecific Radioimmunoconjugates

Contact Info

Product

Resources

About

Dual-Receptor–Targeted Radioimmunotherapy of Human Breast Cancer Xenografts in Athymic Mice Coexpressing HER2 and EGFR Using ¹⁷⁷Lu- or ¹¹¹In-Labeled Bispecific Radioimmunoconjugates