Zongertinib (BI01810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE252799 | GEO | 2024/08/30
REPOSITORIES: GEO
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Project description:Zongertinib (BI01810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers
| PRJNA1062724 | ENA
Project description:UnlabelledFirst-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm(+) sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC is described as proof of principle.SignificanceWe report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented.
| S-EPMC4315625 | biostudies-literature
Project description:BackgroundHER2 (or ERBB2) amplification is an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKI). The benefits of HER2-targeted therapy have been limited. Herein, we investigated the molecular and clinical patterns of HER2 amplification in non-small cell lung cancer (NSCLC) patients during progression on EGFR-TKIs and the potential of combining EGFR-TKI and pyrotinib to overcome resistance.MethodsIn this study, 1,637 NSCLC cases from Geneseeq after progression of EGFR-TKIs were screened and analyzed by next generation sequencing (NGS), in which 48 patients with HER2 amplification were eligible and enrolled. A total of 403 patients from Sun Yat-sen University Cancer Center (SYSUCC) were screened and five patients with concomitant EGFR mutations and HER2 amplification were retrospectively collected to assess the effect of afatinib or combination of EGFR-TKI and pyrotinib.ResultsIn the 48 patients from the Geneseeq cohort, 27 (56.2%) patients suffered from resistance of 1st/2nd generation EGFR-TKI, and 21 (43.8%) patients from 3rd generation. As for the five patients forming the SYSUCC cohort, three patients were treated with afatinib, one achieved partial response (PR) with progression-free survival (PFS) of 6 months and two quickly developed disease progression. Two patients were treated with EGFR-TKIs plus pyrotinib, one receiving gefitinib plus pyrotinib achieved PR with PFS of 8 months and benefited from osimertinib plus pyrotinib for 3 months till data-off; one receiving osimertinib plus pyrotinib achieved SD for 4 months till data-off. The most common co-occurring alteration was TP53 (91.7%) in the mutation profile of the 48 patients from the Geneseeq cohort, and four patients had TP53 co-mutations of the five patients from the SYSUCC cohort.ConclusionIn this study, we detected 7% HER2 amplification present in EGFR-TKIs resistance. Patients with concomitant EGFR mutation and HER2 amplification may derive clinical benefit from therapies that target both EGFR and HER2.
| S-EPMC8609241 | biostudies-literature
Project description: Not available
| S-EPMC7481647 | biostudies-literature
Project description:We separately analyzed the HER2-negative and HER2-positive components of 12 HER2 heterogeneous breast cancers using gene copy number profiling and massively parallel sequencing, and identified potential driver genetic alterations restricted to the HER2-negative cells in each case. Our results indicate that even driver genetic alterations, such as HER2, can be heterogeneously distributed in a cancer, and that the HER2-negative components are likely driven by genetic alterations not present in the HER2-positive components, including BRF2 and DSN1 amplification.
2015-04-16 | GSE67908 | GEO
Project description:Activated HER2 and EGFR stimulate the Ras small GTPases, which in turn primarily activate the MAPK, PI3K-Akt and RalGEF-Ral pathways. While activation of the MAPK and PI3K-Akt pathways downstream of HER2 and EGFR promote mammary tumorigenesis, little is known regarding the role of the RalGEF-Ral pathway. RalGEFs convert the small GTPases RalA and RalB to an active GTP-bound state. Of the two proteins, only activated RalA is transforming, while RalB is more important for cell motility, and hence we investigated the role of RalA in HER2-overexpressing and EGFR-positive breast cancer. We now report that shRNA-mediated knockdown of RalA reduced the in vitro transformed growth and in vivo tumorigenic growth of MDA-MB-231 human breast cancer cells, while knockdown of RalB reduced migration and invasion. Lastly, we demonstrate that expression of activated HER2 increases RalA-GTP levels, and that a number of genes associated with activated RalA are elevated in tumor compared to normal mammary tissue. Taken together, these results suggest a possible role for RalA in mammary tumorigenesis. Four independent cultures of HEK-HT cells stably infected with a retrovirus confirmed to expressed RalAQ72L and four independent cultures of HEK-HT cells stably infected with a control retrovirus RalA activation expression analysis
2016-02-13 | E-GEOD-19295 | biostudies-arrayexpress
Project description:BackgroundHER2-targeted therapies have improved the outcomes of HER2-positive gastric cancer (GC), yet resistance remains a challenge. We sought to explore the effects of reversible and irreversible HER2 tyrosine kinase inhibitors (TKIs) alone or in combination with the HER2-targeting antibody drug conjugate trastuzumab deruxtecan (T-Dxd).MethodsThe effects of HER2-TKIs on HER2 and downstream signaling were evaluated via Western blotting. Proteasomal inhibitors and co-immunoprecipitation assays were performed to explore the role of proteasomal degradation in HER2 expression modulation, and immunofluorescence assays were employed to explore mechanisms of HER2 internalization. The synergistic potential of the irreversible HER2-TKI pyrotinib in combination with T-Dxd was validated using growth and viability assays in anti-HER2-positive GC cell cultures and tumor growth and immunohistochemical staining assays in a mouse xenograft model.ResultsOur study revealed that reversible HER2-TKIs elevated HER2 protein levels, whereas irreversible HER2-TKIs decreased them. Pyrotinib triggered HER2 degradation within the proteasome by promoting ubiquitination and dissociation from HSP90. Furthermore, pyrotinib substantially induced HER2 internalization, which led to improved cellular uptake of T-Dxd. The increased T-Dxd uptake was accompanied by greater efficacy in suppressing the growth of GC cells and enhanced anti-tumor effects in an animal model.ConclusionIn summary, our research reveals the molecular mechanisms of irreversible HER2-TKIs in regulating HER2 protein expression by promoting HER2 internalization. These findings advance our comprehension of targeted therapy for GC and provide a promising therapeutic combination strategy with enhanced efficacy against HER2-positive GC.
| S-EPMC11016512 | biostudies-literature
Project description:Activated HER2 and EGFR stimulate the Ras small GTPases, which in turn primarily activate the MAPK, PI3K-Akt and RalGEF-Ral pathways. While activation of the MAPK and PI3K-Akt pathways downstream of HER2 and EGFR promote mammary tumorigenesis, little is known regarding the role of the RalGEF-Ral pathway. RalGEFs convert the small GTPases RalA and RalB to an active GTP-bound state. Of the two proteins, only activated RalA is transforming, while RalB is more important for cell motility, and hence we investigated the role of RalA in HER2-overexpressing and EGFR-positive breast cancer. We now report that shRNA-mediated knockdown of RalA reduced the in vitro transformed growth and in vivo tumorigenic growth of MDA-MB-231 human breast cancer cells, while knockdown of RalB reduced migration and invasion. Lastly, we demonstrate that expression of activated HER2 increases RalA-GTP levels, and that a number of genes associated with activated RalA are elevated in tumor compared to normal mammary tissue. Taken together, these results suggest a possible role for RalA in mammary tumorigenesis.
2016-02-13 | GSE19295 | GEO
Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients do not benefit from this treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. The series comprised 24 incisional biopsies of breast carcinomas derived from patients that received neoadjuvant trastuzumab based therapy. Gene expression profiling was performed using RNA from frozen core biopsies from 24 patients with primary HER2-positive (HER2+) tumors treated with neoadjuvant chemotherapy and trastuzumab.
2016-03-31 | E-GEOD-62327 | biostudies-arrayexpress
Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients relapse after treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. To search for genes predictive of relapse in HER2-positive breast carcinoma patients treated with adjuvant trastuzumab, we conducted gene expression profiling analysis in 53 cases treated in the clinic with doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF) and trastuzumab. Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded tissues from 53 patients with primary HER2-positive (HER2+) tumors. The series consists in 23 relapsed and 30 non-relapsed cases with similar clinical-pathological characteristics (size, pathological lymph node involvement and estrogen receptor positivity) (3-year median follow up).
2015-10-19 | E-GEOD-55348 | biostudies-arrayexpress