[fam‐] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on <i>HER2</i> amplification

Takegawa, Naoki; Tsurutani, Junji; Kawakami, Hisato; Yonesaka, Kimio; Kato, Ryuichi; Haratani, Koji; Hayashi, Hidetoshi; Takeda, Masayuki; Nonagase, Yoshikane; Maenishi, Osamu; Nakagawa, Kazuhiko

doi:10.1002/ijc.32408

Cited by 73 publications

(49 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1a, b, there was an obvious increase of Annexin V/ PI-positive cells in a dose-dependent manner in SK-BR-3 and BT-474 cells after T-DM1 treatment for 2 days, indicating that T-DM1 induced potent apoptosis in both two breast cancer cells. Specifically, SK-BR-3 cells were more sensitive to T-DM1 than BT-474 cells, which was consistent with HER2 expression levels in these two cells as reported in previous studies (Lewis Phillips et al 2008;Takegawa et al 2019). Caspase-3/7 activation is the key biomarker of apoptosis.…”

Section: T-dm1 Induced Apoptosis In Sk-br-3 and Bt-474 Cellssupporting

confidence: 90%

The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells

Fan

Wang

et al. 2020

AMB Expr

View full text Add to dashboard Cite

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) of trastuzumab and cytotoxic agent emtansine (DM1), has been approved for the therapy of metastatic HER2-positive breast cancer after prior treatment of trastuzumab and taxane. The impressive efficacy exhibited by T-DM1 has heightened the need for more further studies on the underlying mechanisms of T-DM1 cytotoxicity. Previous research suggested that autophagy was crucial for cancer therapy, but the role of autophagy in T-DM1 treatment has not been investigated. Here, we demonstrated for the first time that T-DM1 triggered obvious autophagy in HER2-positive SK-BR-3 and BT-474 breast cancer cells. Blocking autophagy with pharmacological inhibitors chloroquine (CQ) or LY294002 partly reduced T-DM1-induced apoptosis and Caspase-3/7 activation, suggesting that autophagy played an essential role in the cytotoxicity induced by T-DM1 in HER2-positive breast cancer cells. Further investigation demonstrated that Akt/mTOR signaling pathway was involved in T-DM1-induced autophagy in a time-dependent manner. Altogether, our results highlighted the important role of autophagy as a novel mechanism for T-DM1-induced cytotoxicity and elucidated the critical relationships between T-DM1-induced autophagy and apoptosis in human HER2-positive breast cancer cells, which provides novel insight into the underlying anti-tumor mechanism of T-DM1.

show abstract

Section: T-dm1 Induced Apoptosis In Sk-br-3 and Bt-474 Cellssupporting

confidence: 90%

The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells

Fan

Wang

et al. 2020

AMB Expr

View full text Add to dashboard Cite

show abstract

“…Furthermore, the antitumor effect of DXd is basically independent of the absence or presence of other gene alterations such as those that activate alternative pathways (MET or CCNE1 co-amplification) or those that affect downstream signaling components like RAS or RAF, suggesting that trastuzumab deruxtecan may be able to overcome trastuzumab resistance. In our preclinical study, we found that the antitumor effect of trastuzumab deruxtecan was more rapid for HER2-amplified tumors than for those that expressed HER2 without HER2 amplification, possibly as a result of a difference in tumor dependence on HER2 signaling [62]. These preliminary results await clinical confirmation, however.…”

Section: Advantages Of Trastuzumab Deruxtecanmentioning

confidence: 56%

“…In AGC, the concordance between IHC and FISH for detection of HER2 overexpression is moderate, with a value of 83% for the ToGA trial [2], suggesting that a substantial population of patients classified as HER2-negative by FISH are actually positive for HER2 protein expression but do not benefit from current anti-HER2 therapy. In our preclinical study, with the use of engineered cell lines that expressed HER2 protein at various levels in the absence of HER2 amplification, we also demonstrated the efficacy of trastuzumab deruxtecan against tumors that express HER2 but are negative for HER2 amplification [62]. In this case, HER2 may function as a "gate" for the selective passage of DXd, with the antitumor effect being solely due to the cytotoxicity of DXd, not to HER2 signal blockade by trastuzumab.…”

Section: Advantages Of Trastuzumab Deruxtecanmentioning

confidence: 67%

“…Although homogeneity of HER2 amplification and expression is necessary for the success of conventional HER2-targeted therapy, such homogeneity is less frequent for AGC than for breast cancer and is not necessarily required for the success of therapy with trastuzumab deruxtecan. We thus previously showed that trastuzumab deruxtecan is effective not only against tumor cells positive for HER2 protein but also, in the presence of HER2-positive cells, against those negative for such expression [62] (Figure 1). This "bystander killing effect" is likely due to the internalization of trastuzumab deruxtecan by HER2-positive cells ( Figure 1A), the release of DXd into the cytoplasm of these cells ( Figure 1B), and the subsequent transfer of the released DXd into adjacent HER2-negative cells ( Figure 1C) [63].…”

Section: Advantages Of Trastuzumab Deruxtecanmentioning

confidence: 88%

See 1 more Smart Citation

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Mitani

Kawakami

2020

Cancers

Self Cite

View full text Add to dashboard Cite

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies. basis of these results, trastuzumab was approved for AGC with a high HER2 expression level, and trastuzumab-containing regimens are now a standard option for the first-line treatment of such patients, who accounted for 7% to 17% of all individuals with gastric cancer [3-5]. Derivatives of the ToGA Regimen in the First-Line SettingThe ToGA trial adopted a regimen of cisplatin combined with either 5-fluorouracil (5-FU) or capecitabine, whereas subsequent prospective studies found similar treatment outcomes with regimens containing oxaliplatin or tegafur-gimeracil-oteracil (S-1). In a single-arm, nonrandomized phase II trial (HER2-based strategy in stomach cancer (HERBIS)-1) performed in Japan [6], trastuzumab in combination with S-1 plus cisplatin yielded a confirmed ORR of 68%, with a median OS and a median PFS of 16.0 and 7.8 months, respectively, in HER2-positive AGC patients with measurable lesions, with these results being similar to those of the ToGA trial [2]. Similar efficacy was also apparent in AGC patients without measurable lesions (HERBIS-1B study) [7]. Three phase II studies that assessed the combination of trastuzumab with capecitabine plus oxaliplatin reported a median OS, a median PFS, and an ORR of 13.8 to 21.0 months, 7.1 to 9.8 months, and 46.7% to 67.3%, respectively [8][9][10]. Trastuzumab in combination with S-1 plus oxaliplatin was also shown to provide a similar treatment outcome in a phase II study, with a median OS, a median PFS, and an ORR of 18.1 months, 8.8 months, and 70.7%, respectively [11]. A meta-analysis of data from these trials revealed that S-1 or oxaliplatin can substitute effectively for capecitabine or 5-FU or for cisplatin, respectively [12].Immune checkpoint inhibitors such as antibodies to programmed cell death-1 (PD-1) have recently revolutionized treatment strategies for advanced cancer. Given that trastuzumab was found to stimulate T cell responses [13], the combination of trastuzumab-containing regimens with antibodies to PD-1 is receiving attention. A phase II study including 37 patients with HER2-positive AGC treated in the first-line setting with capecitabine, oxaliplatin, and trastuzumab in combination with the anti-PD-1 antibody pembrolizumab reported an ORR of 83%, with a median PFS of 11.4 months and a median ...

show abstract

“…26,27 Clinical data indicated a manageable safety profile and preliminary efficacy in heavily pre-treated patients (including those relapsing after T-DM1 protocols) with breast and gastric cancer. [28][29][30] Enhertu's approval was based on the results of a clinical trial enrolling 184 patients with ErbB2-positive, unresectable and/or metastatic breast and gastric cancer. These patients were heavily pretreated, having received between two and 17 treatments prior to receiving Enhertu.…”

Section: Anti-erbb2 Approved Productsmentioning

confidence: 99%

Anti-ErbB2 immunotherapeutics: struggling to make better antibodies for cancer therapy

Santis

2020

mAbs

View full text Add to dashboard Cite

Over the past 3 decades, monoclonal antibodies and their related derivatives, including recently approved antibody-drug conjugates, conquered a central role in cancer therapy because of their contribution to improve survival, time to progression and quality of life of patients compared to chemotherapy protocols. This review summarizes information on approved original and biosimilar products, as well as investigational antibody-based therapeutics, targeting ErbB2. This target has been selected as a paradigmatic example because of its relevant role in sustaining the malignancy of major cancer diseases including, breast, gastric and other chemotherapy-resistant solid tumors. This work analyzes the drivers affecting research and development of next-generation anti-ErbB2 immunotherapeutics, taking into account unmet medical needs and pharmacoeconomic issues related to sustainability. The analysis may help with the design of future research and development strategies.

show abstract

[fam‐] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification

Cited by 73 publications

References 26 publications

The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells

The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Anti-ErbB2 immunotherapeutics: struggling to make better antibodies for cancer therapy

Contact Info

Product

Resources

About