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A Study of T-DXd for the Treatment of Solid Tumors Harboring HER2 Activating Mutations

ABSTRACT: This is an open-label, multi-center, single arm, Phase II study to evaluate the efficacy and safety of T-DXd for the treatment of unresectable and/or metastatic solid tumors harboring specific HER2 activating mutations regardless of tumor histology. The target population are patients who have progressed following prior treatment or who have no satisfactory alternative treatment options, including approved second line therapies in the specific tumor type. Pre-specified HER2 mutations will be locally assessed using NGS tests or alternative methods. Prior HER2 targeting therapy is permitted.

DISEASE(S): Treatment Of Unresectable And/or Metastatic Solid Tumors Harboring Specific Her2 Activating Mutations Regardless Of Tumor Histology.,Advanced Solid Tumors With Her2,Advanced Solid Tumors With Her2 Mutation,eg:colorectal,urothelial,gastric, Hepatobiliary,endometrial,melanoma,ovarian,cervical,salivary Gland,pancreatic,breast,Solid Tumors,Neoplasms

PROVIDER: 2358501 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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DETERMINE Trial Treatment Arm 04: Trastuzumab in Combination With Pertuzumab in Adult, Teenage/Young Adult and Paediatric Patients With Cancers With HER2 Amplification or Activating Mutations

Project description:This clinical trial is looking at a combination of drugs called trastuzumab and pertuzumab. This combination of drugs is approved as standard of care treatment for adult patients with metastatic breast cancer. This means it has gone through clinical trials and been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. Trastuzumab and pertuzumab work in patients with these types of cancers which have a molecular alteration called HER2 amplification or HER2 activating mutation. Investigators now wish to find out if it will be useful in treating patients with other cancer types which are also HER2 amplified or HER2 mutated. If the results are positive, the study team will work with the NHS and the Cancer Drugs Fund to see if these drugs can be routinely accessed for patients in the future. This trial is part of a trial programme called DETERMINE. The programme will also look at other anti-cancer drugs in the same way, through matching the drug to rare cancer types or ones with specific mutations.

| 12849 | ecrin-mdr-crc

Breast cancer mutations HER2V777L and PIK3CAH1047R activate the p21-CDK4/6 –Cyclin D1 axis driving tumorigenesis and drug resistance.

Project description:In metastatic breast cancer, HER2 activating mutations frequently co-occur with mutations in the PIK3CA, TP53, or E-cadherin genes. Of these co-occurring mutations, HER2 and PIK3CA mutations are the most prevalent gene pair, with approximately 40% of HER2 mutated breast cancers also having activating mutations in PIK3CA. To study the effects of co-occurring HER2 and PIK3CA mutations, we bred genetically engineered mice with the HER2V777L; PIK3CAH1047R transgenes (HP mice) and studied the resulting breast cancers both in vivo as well as ex vivo using cancer organoids.

2023-07-21 | GSE216871 | GEO

Potent and EGFRWT Sparing HER2 Inhibitors for the Treatment of HER2 Exon 20 Insertion-Driven Tumors

Project description:Activating mutations in ERBB receptors act as oncogenes in non-small cell lung cancer (NSCLC). Besides the more prevalent epidermal growth factor receptor (EGFR) activating mutations, oncogenic variants in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of NSCLC patients. HER2 oncogenic mutations in NSCLC predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinically approved and currently tested tyrosine kinase inhibitors are limited by either insufficient potency on exon 20 altered HER2 and/or their insufficient selectivity against EGFR wild type (EGFR WT) – a major cause of dose limiting toxicity. We report herein the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing EGFR WT. The new inhibitors presented in this study reduce tumor cell survival and proliferation in vitro, and result in regressions in in vivo preclinical xenograft models of HER2 exon 20 mutant NSCLC as well as inhibition of downstream signaling. Our results suggest that HER2 exon 20 insertion driven tumors can be effectively treated by a potent and highly selective HER2 inhibitor while sparing EGFR WT. The new inhibitors described in this study pave the way for testing potent HER2 selective inhibitors in HER2 mutant NSCLC patients and may offer an additional therapeutic option for these patients.

2022-03-19 | GSE181673 | GEO

Activating NOTCH1 mutations increase T-ALL cells’ chemosensitivity by altering PREX2-AKT pathway

Project description:Mutations on NOTCH1 gene are the most commonly found mutations in T-cell acute lymphoblastic leukemia (T-ALL) and they are reported to be favorable indicators for T-ALL patients' prognosis. However, the effects of activating NOTCH1 mutations on T-ALL's chemosensitivity have not been studied. We reported that NOTCH1 inhibition by gamma-secretase inhibitors or shRNA knockdown in MOLT-3 cells could reduce the T-ALL cells' sensitivity to chemotherapeutic drugs. However, this effect was absent in Jurkat and CUTLL1 cells. We further demonstrated that NOTCH1 inhibition could activate the PI3K-AKT pathway in a cell specific pattern similar as their effects on chemosensitivity. RNA-seq revealed that Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 2 (PREX2) is a target gene of NOTCH1 and may mediate the effects of activating NOTCH1 mutations on chemosensitivity. Consistently, we proved that overexpression of PREX2 could mimic the effects of NOTCH1 inhibition on chemosensitivity. Our study has highlighted the effects of activating NOTCH1 mutations on T-ALL's chemosensitivity by altering PREX2-AKT pathway, which may explain the favorable effects of NOTCH1 mutations on T-ALL patients' prognosis, as well as provided potential targets to sensitize T-ALL cells to chemotherapy.

2021-07-07 | GSE179425 | GEO

Activating Mutations in PIK3CA result in Widespread Modulation of the Tyrosine Phosphoproteome

Project description:The human oncogene PIK3CA is frequently mutated in human cancers. The two hotspot mutations in PIK3CA, E545K and H1047R, have been shown to regulate widespread signaling events downstream of AKT. However, the impact of these activating mutations on the tyrosine phosphorylation signaling in the cell has not been studied. Here, we performed a global phosphotyrosine profiling using isogenic knockin cell lines containing these activating mutations. We identified 824 unique phosphopeptides from 308 proteins. We found a surprisingly widespread modulation of tyrosine phosphorylation levels of proteins in the knockin mutant cells, with many of the regulated proteins involved in important biological processes, including those in the cytoskeletal migration pathways and kinase regulated signaling. We observed a widespread modulation of the tyrosine kinome, with 24 of the tyrosine kinases showing either upregulation or downregulation in phosphorylation levels. Many of the regulated phosphosites that we identified were located in the kinase domain or the canonical activating sites, indicating that the kinases were active and hence their downstream signaling pathways. Our study thus shows that the activating mutations in PIK3CA result in widespread tyrosine signaling regulation, in addition to the serine/threonine signaling pathways activated by the canonical PI3K-AKT axis.

2018-10-24 | PXD001460 | Pride

ERBB2/HER2 transmembrane and juxtamembrane domain mutations in cancer

Project description:In this study, we identified several recurrent activating HER2 somatic mutations in transmembrane and juxtamembrane domain in multiple cancers and demonstrate that patients carryingthese mutations are candidates for anti-HER2 therapy. We have also identified a germline mutation in HER2 transmembrane domain.

| EGAS00001003213 | EGA

Recurrent activating STAT5B N642H mutations in myeloid neoplasms with eosinophilia

Project description:Recurrent activating STAT5B N642H mutations in myeloid neoplasms with eosinophilia

| PRJEB30454 | ENA

rare HER2 missense mutations promote the oncogenic signaling and migration of breast cancer

Project description:Proteomic and phosphoproteomic data for rare HER2 missense mutations

2023-03-20 | PXD040988 |

Genomic alterations activating KLF5

Project description:Genomic alterations activating KLF5

| PRJNA349438 | ENA

Activating mutations remodeled the chromatin accessibility landscape to drive distinct regulatory networks in KMT2A-rearranged acute leukemia

Project description:Activating FLT3 and RAS mutations are common in KMT2A-rearrangement (KMT2A-r) leukemia, but their functions in remodeling the chromatin accessibility is unknow. Using a retroviral acute myeloid leukemia (AML) mouse model driven by KMT2A::MLLT3, we show that FLT3/ITD, FLT3/N676K, and NRAS/G12D rewired the chromatin accessibility landscape and associated transcriptional networks. FLT3/N676K and NRAS/G12D mutations resulted in similar networks which were distinct from those mediated by FLT3/ITD. Motif analysis revealed that the AP-1 family transcription factors had a role in KMT2A::MLLT3 leukemia with FLT3/N676K and NRAS/G12D, whereas RUNX1/2 and Stat5a/Stat5b were active in the presence of FLT3/ITD. Further, transcriptional programs related with stemness, activation of T-cells and negative regulation of NK-cells were activated in the presence of NRAS/G12D and FLT3/N676K. Taken together, activating mutations established mutation-specific changes in the epigenetic landscape that led to changes in the transcriptional programs driven by specific transcription factors.

2024-09-01 | GSE248468 | GEO

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