YES1 amplification confers trastuzumab–emtansine (T-DM1) resistance in HER2-positive cancer

Wang, Lei; Wang, Quanren; Xu, Piaopiao; Li, Fu; Li, Yun; Fu, Haoyu; Quan, Hui; Lou, Liguang

doi:10.1038/s41416-020-0952-1

Cited by 20 publications

(25 citation statements)

References 51 publications

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“…4G). Taken together, we demonstrate that by destabilizing ERBB2, that we controlled and downregulated YES1 and WNK1 that are well known causes of drug resistance in ERBB2+ trastuzumab drug resistant and in osimertinib resistant EGFR T790M lung cancer (28)(29)(30)(31).…”

Section: S2a-b List S2)mentioning

confidence: 59%

Destabilized 3’UTR ARE therapeutically degrades ERBB2 in drug-resistant ERBB2+ cancer models

Awah

Glemaud

Levine

et al. 2022

Preprint

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Breast, lung, and colorectal cancer resistance to molecular targeted therapy is a major challenge and unfavorably impacts clinical outcomes, leading to hundreds of thousands of deaths yearly. In ERBB2+ cancers regardless of the tissue of origin, ERBB2 is the driver oncogene of resistance. We discovered that the ERBB2+ cancers are enriched with poly U sequences on their 3UTR AU rich elements which are mRNA stabilizing sequences. We developed a novel technology, in which we engineered these ERBB2 mRNA stabilizing sequences to unstable forms and specifically controlled and degraded ERBB2 transcript and protein across multiple cancer types both in the wild-type and drug resistance settings in vitro and in vivo, offering a unique novel modality to control ERBB2 and other pervasive oncogenic signals where other therapies fail.

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Section: S2a-b List S2)mentioning

confidence: 59%

Destabilized 3’UTR ARE therapeutically degrades ERBB2 in drug-resistant ERBB2+ cancer models

Awah

Glemaud

Levine

et al. 2022

Preprint

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“…The possibility that YES1 might serve as a therapeutic target for breast cancer therapy as a means of overcoming drug resistance has already been reported. Previous studies showed the role of YES1 amplification in T-DM1 [ 22 ], trastuzumab and lapatinib [ 7 ], and neratinib [ 19 ] regimens. Among members of the Src family, YES1 expression showed the highest association with poor outcomes in patients with non-small cell lung cancer [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development

Fujihara

Shien

et al. 2021

IJMS

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Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1.

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Section: Clinical Use Controversiesmentioning

confidence: 99%

“…32 Wang et al found that the cells that were resistant to ado-trastuzumab emtansine had overexpressed Yes, which in turn activated EGFR, PI3K, and MAPK pathways. 33 They suggested using Yes and HER2 inhibitors together in attempts to better counteract resistance developed to ado-trastuzumab emtansine. 33 Another agent that was found to be able to overcome the resistance is SYD985, a secondgeneration antibody drug conjugate.…”

Section: Clinical Use Controversiesmentioning

confidence: 99%

“…33 They suggested using Yes and HER2 inhibitors together in attempts to better counteract resistance developed to ado-trastuzumab emtansine. 33 Another agent that was found to be able to overcome the resistance is SYD985, a secondgeneration antibody drug conjugate. 34 D'Amico et al suggested that dihydroartemisinin increases the effect of ado-trastuzumab emtansine on microtubules and overall aggressive resistant HER2 tumors, which supports clinical development and testing of dihydroartemisinin and ado-trastuzumab emtansine combination.…”

Section: Clinical Use Controversiesmentioning

confidence: 99%

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The role of ado-trastuzumab emtansine in current clinical practice

Turshudzhyan

2020

J Oncol Pharm Pract

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Objective This review reflects the literature from 2019 to 2020 on ado-trastuzumab emtansine’s (T-DM1) therapeutic use, clinical controversies, and newest perspectives on use. Data sources: PubMed was used as a database. Search “ado-trastuzumab emtansine” on June 11th, 2020 resulted in 57 publications: 20 clinical trials, two metanalysis, six randomized controlled studies, 13 reviews, and two systematic reviews. Of the 57 publications, 34 were descriptive of the topic in question and were used for this review. Data summary: T-DM1 is now used for patients with HER2 breast cancer who have residual disease post surgery after neoadjuvant chemotherapy (KATHERINE trial). Initial success prompted KRISTINE trial, which investigated whether T-DM1 can be used as a neoadjuvant therapy. While it did have fewer adverse events, T-DM1 was inferior to chemotherapy in treating early breast cancer. Noted shortcomings of the drug were toxicity limited Cmax, slow rate of internalization, lack of payload bystander effects, and number of resistance mechanisms. Proposed solutions were pre-treatment with metformin to augment drug internalization by the cell, use of second generation anti-HER2 antibody-drug conjugates to overcome developing resistance, payload swapping to increase bystander effect. Conclusions While T-DM1 has fewer side-effects, it is inferior to chemotherapy in early breast cancer treatment. More research should be done to overcome resistance pathways, identify rate-limiting intracellular processing pathways, improve bystander, and enhance internalization of the drug. Until more research is done, T-DM1 will continue to be used in HER2 positive breast cancer as well as a few other HER2 expressing tumors that fail to respond to neoadjuvant therapy.

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YES1 amplification confers trastuzumab–emtansine (T-DM1) resistance in HER2-positive cancer

Cited by 20 publications

References 51 publications

Destabilized 3’UTR ARE therapeutically degrades ERBB2 in drug-resistant ERBB2+ cancer models

Destabilized 3’UTR ARE therapeutically degrades ERBB2 in drug-resistant ERBB2+ cancer models

YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development

The role of ado-trastuzumab emtansine in current clinical practice

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