HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Xu, Xiaowei; Angelis, Carmine De; Burke, Kathleen A.; Nardone, Agostina; Hu, Huizhong; Qin, Lanfang; Veeraraghavan, Jamunarani; Sethunath, Vidyalakshmi; Heiser, Laura M.; Wang, Nicholas; Ng, Charlotte K.Y.; Chen, Edward S.; Renwick, Alexander; Wang, Tao; Nanda, Sarmistha; Shea, Martin J.; Mitchell, Tamika; Rajendran, Mahitha; Waters, Ian; Zabransky, Daniel J.; Scott, Kenneth L.; Gutiérrez, Carolina; Nagi, Chandandeep; Geyer, Felipe C.; Chamness, Gary C.; Park, Ben Ho; Shaw, Chad A.; Hilsenbeck, Susan G.; Rimawi, Mothaffar F.; Gray, Joe W.; Weigelt, Britta; Reis‐Filho, Jorge S.; Osborne, C. Kent; Schiff, Rachel

doi:10.1158/1078-0432.ccr-16-2191

Cited by 92 publications

(90 citation statements)

References 57 publications

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“…Although afatinib, neratinib, and osimertinib were found to be effective against most of the ERBB2 mutants analyzed in this study, several ERBB2 mutants, such as L755 mutations and exon 20 insertions, showed different sensitivities to the three drugs. Whereas some studies have suggested that afatinib and neratinib are effective against L755S (11,18,46), our in vitro study showed that the IC 50 values of the two drugs against L755P/S mutations were relatively higher than those against other ERBB2 mutants. Moreover, a low-dose treatment with afatinib (8 mg/kg) could not inhibit the in vivo growth of the tumors with ERBB2(L755P).…”

Section: Discussioncontrasting

confidence: 88%

High-Throughput Functional Evaluation of Variants of Unknown Significance in ERBB2

Nagano

Kohsaka

Ueno

et al. 2018

Clinical Cancer Research

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The advent of next-generation sequencing technologies has enabled the identification of several activating mutations of Erb-B2 receptor tyrosine kinase 2 (ERBB2) among various cancers. However, the significance of infrequent mutations has not been fully investigated. Herein, we comprehensively assessed the functional significance of the mutations in a high-throughput manner. We evaluated the transforming activities and drug sensitivities of 55 nonsynonymous mutations using the mixed-all-nominated-in-one (MANO) method. G776V, G778_S779insG, and L841V were newly revealed to be activating mutations. Although afatinib, neratinib, and osimertinib were shown to be effective against most of the mutations, only osimertinib demonstrated good efficacy against L755P and L755S mutations, the most common mutations in breast cancer. In contrast, afatinib and neratinib were predicted to be more effective than other inhibitors for the A775_776insYVMA mutation, the most frequent mutation in lung cancer. We surveyed the prevalence of concurrent mutation with gene amplification and found that approximately 30% of ERBB2-amplified urothelial carcinomas simultaneously carried mutations, altering their sensitivity to trastuzumab, an mAb against ERBB2. Furthermore, the MANO method was applied to evaluate the functional significance of 17 compound mutations within reported in the COSMIC database, revealing that compound mutations involving L755S were sensitive to osimertinib but insensitive to afatinib and neratinib. Several mutations showed varying sensitivities to ERBB2-targeted inhibitors. Our comprehensive assessment of mutations offers a fundamental database to help customize therapy for ERBB2-driven cancers.We identified several mutations as activating mutations related to tumorigenesis. In addition, our comprehensive evaluation revealed that several mutations showed varying sensitivities to ERBB2-targeted inhibitors, and thus, the functional significance of each variant should be interpreted precisely to design the best treatment for each patient. .

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Section: Discussioncontrasting

confidence: 88%

High-Throughput Functional Evaluation of Variants of Unknown Significance in ERBB2

Nagano

Kohsaka

Ueno

et al. 2018

Clinical Cancer Research

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“…In this series, endocrine resistance was successfully reversed in 1 patient with the addition of neratinib. In HER2-amplified cancers, acquisition of activating HER2 mutations has also been reported by multiple groups as a potential resistance mechanism to HER2 therapy (35,36). Interestingly, we have previously shown that at least a subset of these acquired HER2 mutations in HER2-positive breast cancers retain sensitivity to neratinib, despite conferring resistance to HER2-directed monoclonal antibodies and reversible kinase inhibitors (11).…”

Section: Discussionmentioning

confidence: 55%

Efficacy and Determinants of Response to HER Kinase Inhibition inHER2-Mutant Metastatic Breast Cancer

et al. 2020

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HER2 mutations defi ne a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversi ble pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER + patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2 -activating events , as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefi t from neratinib. Collectively, these data defi ne HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations defi ne a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modifi ed by the presence of concurrent activating genomic events in the pathway. These fi ndings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defi ned subset of breast cancer.

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“…identified 12 novel or previously reported HER family mutations in primary breast tumors, and showed that patients whose primary tumors harbor these mutations demonstrated poor response to trastuzumab-based chemotherapy in the metastatic setting(23). Importantly, in our very recent study, we have shown in preclinical HER2-positive breast cancer models that the most common HER2 mutation, L755S residing in the kinase domain of the receptor, reactivates HER2 signaling and thereby constitutes an endogenous mechanism of acquired resistance to lapatinib and trastuzumab-containing HER2-targeted therapies(25). Interestingly, the Zuo et al .…”

Section: Oncogenic Her2 Addictionmentioning

confidence: 99%

“…The suggested HER2 L755S-conferred conformational change in the HER2 kinase domain renders it unable to bind lapatinib. In this regard, our recent study suggests that the HER2 L755S-mediated resistance to various anti-HER2 regimens can be partly overcome by irreversible HER1/2 inhibitors, such as afatinib and neratinib(25). Thus, the significance of these HER2 mutations in primary and acquired resistance, the implementation of more sensitive methods to identify them in HER2-positive tumors with HER2 gene amplification, and the therapeutic efficacy of the irreversible inhibitors in this setting need to be further explored.…”

Section: Oncogenic Her2 Addictionmentioning

confidence: 99%

De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance

et al. 2017

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Summary Overexpression and/or gene amplification of HER2, a crucial member of the HER family of four receptors, occur in about 15–20% of breast cancers and define an aggressive subtype of the disease. Activated HER homo and heterodimers govern a complex and redundant downstream signaling network that regulates cell survival and metastasis. Despite treatment with effective HER2-targeted therapies, many HER2-positive tumors fail to respond, or initially respond but eventually develop resistance. One of the upfront reasons for this treatment failure is failure to accurately select the tumors that are truly dependent on HER2 for survival and so would benefit the most from HER2-targeted therapy. In these truly HER2-addicted tumors (i.e. physiologically dependent), resistance could be the result of an incomplete inhibition of signaling at the HER receptor layer. In this regard, preclinical and clinical studies have documented the superiority of combination anti-HER2 therapy over single agent therapy to achieve a more comprehensive inhibition of the various HER receptor dimers. HER2 can be further activated or reactivated by mutations or other alterations in HER2 itself, or in other HER family members. Even when a complete and sustained HER inhibition is achieved, resistance to anti-HER therapy can arise by other somewhat dominant mechanisms, including preexisting or emerging alternative signaling pathways such as the estrogen receptor, deregulated downstream signaling components, especially of the PI3K pathway, and the tumor immune microenvironment. Most of the clinical trials that have investigated the efficacy of anti-HER2 therapies took place in the background of aggressive chemotherapy regimens, thus confounding the identification of key factors of resistance to the anti-HER2 treatments. Recent studies, however, have suggested that some HER2-amplified tumors may benefit from anti-HER2 therapy combined with only single chemotherapy agent or in the absence of any chemotherapy. This de-escalation approach, a promising therapeutic strategy, is currently being explored in the clinic. In this review, we summarize the major molecular determinants that play a crucial role in influencing tumor response and resistance to HER2-targeted therapy, and discuss the growing need for patient stratification in order to facilitate the development of de-escalation strategies using HER2-targeted therapy alone with no chemotherapy.

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HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Cited by 92 publications

References 57 publications

High-Throughput Functional Evaluation of Variants of Unknown Significance in ERBB2

High-Throughput Functional Evaluation of Variants of Unknown Significance in ERBB2

Efficacy and Determinants of Response to HER Kinase Inhibition inHER2-Mutant Metastatic Breast Cancer

De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance

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