Adaptive resistance to trastuzumab impairs response to neratinib and lapatinib through deregulation of cell death mechanisms

Rios‐Luci, Carla; Dı́az-Rodrı́guez, Elena; Gandullo-Sánchez, Lucía; Díaz-Gil, Laura; Ocaña, Alberto; Pandiella, Atanasio

doi:10.1016/j.canlet.2019.11.026

Cited by 12 publications

(13 citation statements)

References 35 publications

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“…We complemented the above studies by using another model of secondary resistance to trastuzumab derived from a PDX (PDX118) initially sensitive to trastuzumab (Rios‐Luci et al , ). To that end, a PDX118 tumor grown in a mouse was dissected and cells disaggregated and placed in culture.…”

Section: Resultsmentioning

confidence: 99%

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HER3 targeting with an antibody‐drug conjugate bypasses resistance to anti‐HER2 therapies

et al. 2020

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Despite impressive clinical benefit obtained with anti-HER2-targeted therapies, in advances stages, especially in the metastatic setting, HER2-positive tumors remain incurable. Therefore, it is important to develop novel strategies to fight these tumors, especially when they become resistant to available therapies. We show here that the anti-HER3 antibody-drug conjugate EV20/MMAF exerted potent antitumoral properties against several models of primary resistance and secondary resistance to common anti-HER2 available therapies, including trastuzumab, lapatinib, neratinib, and trastuzumab-emtansine. HER3 was expressed in these HER2 + breast cancer cells and knockdown experiments demonstrated that HER3 expression was required for the action of EV20/MMAF. In mice injected with trastuzumab-resistant HER2 + cells, a single dose of EV20/MMAF caused complete and long-lasting tumor regression. Mechanistically, EV20/ MMAF bound to cell surface HER3 and became internalized to the lysosomes. Treatment with EV20/MMAF caused cell cycle arrest in mitosis and promoted cell death through mitotic catastrophe. These findings encourage the clinical testing of EV20/MMAF for several indications in the HER2 + cancer clinic, including situations in which HER2 + tumors become refractory to approved anti-HER2 therapies.

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Section: Resultsmentioning

confidence: 99%

“…Cell proliferation was analyzed by cell counting assays (Rios‐Luci et al , ). Briefly, cells were seeded in 6‐well plates, and 24 h later, the medium was replaced with complete medium containing the desired drugs.…”

Section: Methodsmentioning

confidence: 99%

HER3 targeting with an antibody‐drug conjugate bypasses resistance to anti‐HER2 therapies

et al. 2020

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“…Cancer progression including proliferation, metastasis and chemoresistance to drugs, has become serious obstacles in cancer therapy 1 . Although multiple therapeutic manners including operation, targeted therapy, chemotherapy, and radiotherapy have shown satisfactory performance, progression occurs since cancer cells dysregulate apoptosis pathways via various manners 2 , 3 . Therefore, new types of cancer therapy or drugs that eliminate cancer cells are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

“…Ferroptosis is a recently recognized form of programmed cell death that relies on excess intracellular ROS and consequent lipid peroxidation 198 . Ferroptosis has been successfully applied to limit tumor growth and overcome the resistance of cancer cells to apoptosis, indicating that it may be useful as a new therapeutic approach 3 . Nevertheless, the application of ferroptosis inducers in cancer therapy is limited, mainly because the specific mechanisms underlying ferroptosis remain unexplored.…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between noncoding RNAs and ferroptosis: new dawn for overcoming cancer progression

Zhang

Wang

et al. 2020

Cell Death Dis

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Cancer progression including proliferation, metastasis, and chemoresistance has become a serious hindrance to cancer therapy. This phenomenon mainly derives from the innate insensitive or acquired resistance of cancer cells to apoptosis. Ferroptosis is a newly discovered mechanism of programmed cell death characterized by peroxidation of the lipid membrane induced by reactive oxygen species. Ferroptosis has been confirmed to eliminate cancer cells in an apoptosis-independent manner, however, the specific regulatory mechanism of ferroptosis is still unknown. The use of ferroptosis for overcoming cancer progression is limited. Noncoding RNAs have been found to play an important roles in cancer. They regulate gene expression to affect biological processes of cancer cells such as proliferation, cell cycle, and cell death. Thus far, the functions of ncRNAs in ferroptosis of cancer cells have been examined, and the specific mechanisms by which noncoding RNAs regulate ferroptosis have been partially discovered. However, there is no summary of ferroptosis associated noncoding RNAs and their functions in different cancer types. In this review, we discuss the roles of ferroptosis-associated noncoding RNAs in detail. Moreover, future work regarding the interaction between noncoding RNAs and ferroptosis is proposed, the possible obstacles are predicted and associated solutions are put forward. This review will deepen our understanding of the relationship between noncoding RNAs and ferroptosis, and provide new insights in targeting noncoding RNAs in ferroptosis associated therapeutic strategies.

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“…To measure HER2 surface levels, cells were processed as detailed in [ 29 ]. In brief, detached cells were incubated with trastuzumab 10 nM for 30 min and then with anti-human Cy3-conjugated secondary antibody (1:80 dilution).…”

Section: Methodsmentioning

confidence: 99%

Modelling hypersensitivity to trastuzumab defines biomarkers of response in HER2 positive breast cancer

Díaz-Gil

Brasó-Maristany

Locatelli

et al. 2021

J Exp Clin Cancer Res

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Background Trastuzumab-based therapies are the therapeutic option for HER2 positive (HER2+) breast cancer. HER2 amplification is the only biomarker validated for trastuzumab-based therapies. However, a proportion of tumors become refractory during treatment course. For this reason, the finding of new biomarkers beyond HER2 overexpression to identify patients who would benefit most from trastuzumab regimens is of outstanding importance. Methods Models of trastuzumab-resistant or hypersensitive cells were generated by exposure to trastuzumab. Cell surface, total HER2, and analyses of proteins involved in cell cycle or apoptosis were analyzed by western blotting. Cell proliferation was analyzed by cell counting, cell cycle and apoptosis was evaluated by FACS. Transcriptomic characterization of the cellular models was performed using bioinformatic online tools, and clinico-genomic analyses were performed using the PAMELA clinical trial data. Results Besides differing in sensitivities to trastuzumab, the different cellular models also showed distinct response to other anti-HER2 drugs (lapatinib, neratinib, pertuzumab and T-DM1) used in the clinic. That differential effect was not due to changes in cell surface, total or activated HER2. Trastuzumab caused important induction of cell death in hypersensitive cells but not in parental or resistant cells. Transcriptomic analyses of these cellular models together with querying of online databases allowed the identification of individual genes and gene signatures that predicted prognosis and trastuzumab response in HER2+ breast cancer patients. Conclusion The identification of trastuzumab response biomarkers may be used to select patients particularly sensitive to facilitate the use of trastuzumab-based therapies and refine follow-up guidelines in patients with HER2+ tumors.

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Adaptive resistance to trastuzumab impairs response to neratinib and lapatinib through deregulation of cell death mechanisms

Cited by 12 publications

References 35 publications

HER3 targeting with an antibody‐drug conjugate bypasses resistance to anti‐HER2 therapies

HER3 targeting with an antibody‐drug conjugate bypasses resistance to anti‐HER2 therapies

Crosstalk between noncoding RNAs and ferroptosis: new dawn for overcoming cancer progression

Modelling hypersensitivity to trastuzumab defines biomarkers of response in HER2 positive breast cancer

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