HER2-Mediated Internalization of Cytotoxic Agents in<i>ERBB2</i>Amplified or Mutant Lung Cancers

Li, Bob T.; Michelini, Flavia; Misale, Sandra; Cocco, Emiliano; Baldino, Laura; Cai, Yanyan; Shifman, Sophie; Tu, Hai‐Yan; Myers, Michael L.; Xu, Chong-Rui; Mattar, Marissa S.; Khodos, Inna; Little, Megan; Qeriqi, Besnik; Weitsman, Gregory; Wilhelm, Clare; Lalani, Alshad S.; Diala, Irmina; Freedman, Rachel A.; Lin, Nancy U.; Solit, David B.; Berger, Michael F.; Barber, Paul R.; Ng, Tony; Offin, Michael; Isbell, James M.; Jones, David R.; Yu, Helena A.; Thyparambil, Sheeno; Liao, Wei‐Li; Bhalkikar, Anuja; Cecchi, Fabiola; Hyman, David M.; Lewis, Jason S.; Buonocore, Darren J.; Ho, Alan L.; Makker, Vicky; Reis‐Filho, Jorge S.; Razavi, Pedram; Arcila, Maria E.; Kris, Mark G.; Poirier, John T.; Shen, Ronglai; Tsurutani, Junji; Ulaner, Gary A.; Stanchina, Elisa de; Rosen, Neal; Rudin, Charles M.; Scaltriti, Maurizio

doi:10.1158/2159-8290.cd-20-0215

Cited by 199 publications

(159 citation statements)

References 44 publications

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“…Similarly, Li et al examined the three TKIs in combination with T-DM1. 35 Co-treatment with neratinib and T-DM1 in HER2 -amplified or HER2 -mutated cell lines enhanced HER2 ubiquitination and internalisation, thereby increasing T-DM1 activity. This seems to be specific to the irreversible inhibitor, as the addition of lapatinib or tucatinib to T-DM1 did not increase HER2 ubiquitination in vitro.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors

et al. 2021

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Background Human epidermal growth factor 2 (HER2/ERBB2) is frequently amplified/mutated in cancer. The tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib are FDA-approved for the treatment of HER2-positive breast cancer. Direct comparisons of the preclinical efficacy of the TKIs have been limited to small-scale studies. Novel biomarkers are required to define beneficial patient populations. Methods In this study, the anti-proliferative effects of the three TKIs were directly compared using a 115 cancer cell line panel. Novel TKI response/resistance markers were identified through cross-analysis of drug response profiles with mutation, gene copy number and expression data. Results All three TKIs were effective against HER2-amplified breast cancer models; neratinib showing the most potent activity, followed by tucatinib then lapatinib. Neratinib displayed the greatest activity in HER2-mutant and EGFR-mutant cells. High expression of HER2, VTCN1, CDK12, and RAC1 correlated with response to all three TKIs. DNA damage repair genes were associated with TKI resistance. BRCA2 mutations were correlated with neratinib and tucatinib response, and high expression of ATM, BRCA2, and BRCA1 were associated with neratinib resistance. Conclusions Neratinib was the most effective HER2-targeted TKI against HER2-amplified, -mutant, and EGFR-mutant cell lines. This analysis revealed novel resistance mechanisms that may be exploited using combinatorial strategies.

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Section: Discussionmentioning

confidence: 99%

Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors

et al. 2021

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“…Li et al 44 recently reported that the HER2 antibody drug conjugate ado-trastuzumab emtansine (T-DM1) has significant clinical activity in HER2-mutant lung cancer, even in tumors with low HER2 expression. One hypothesis as to why HER2-mutant tumors with low HER2 expression are sensitive to T-DM1 is that mutation of HER2 may increase the efficiency of receptor internalization following antibody binding 45 . Consistent with this finding, the UCC14-PDX was highly sensitive to DS-8201a, a HER2 antibody drug conjugate, which was recently approved by the FDA for unresectable or metastatic HER2-positive breast cancer 38 .…”

Section: Discussionmentioning

confidence: 99%

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Kim

Audenet

et al. 2020

Nat Commun

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Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of diseasespecific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.

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“…Responses were seen across all HER2 mutation subtypes. In a recent analysis of this study including an additional expansion cohort, the results of a total of 49 patients with HER2-amplified and/or -mutated tumors were reported [ 195 ]. The ORR was 50% in both cohorts.…”

Section: Her2 Alterationsmentioning

confidence: 99%

Targeted Therapy in Advanced and Metastatic Non-Small Cell Lung Cancer. An Update on Treatment of the Most Important Actionable Oncogenic Driver Alterations

König

Prince

Rothschild

2021

Cancers

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Due to groundbreaking developments and continuous progress, the treatment of advanced and metastatic non-small cell lung cancer (NSCLC) has become an exciting, but increasingly challenging task. This applies, in particular, to the subgroup of NSCLC with oncogenic driver alterations. While the treatment of epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged NSCLC with various tyrosine kinase inhibitors (TKIs) is well-established, new targets have been identified in the last few years and new TKIs introduced in clinical practice. Even for KRAS mutations, considered for a long time as an “un-targetable” alteration, promising new drugs are emerging. The detection and in-depth molecular analysis of resistance mechanisms has further fueled the development of new therapeutic strategies. The objective of this review is to give a comprehensive overview on the current landscape of targetable oncogenic alterations in NSCLC.

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HER2-Mediated Internalization of Cytotoxic Agents inERBB2Amplified or Mutant Lung Cancers

Cited by 199 publications

References 44 publications

Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors

Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Targeted Therapy in Advanced and Metastatic Non-Small Cell Lung Cancer. An Update on Treatment of the Most Important Actionable Oncogenic Driver Alterations

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