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Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers
Timothy P DiPeri1, Kurt W Evans2, Maria Gabriela Raso3
1Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
Purpose:
Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy.
Experimental Design:
Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC. In vitro, CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to combinatorial therapy with various treatment regimens, followed by tumor growth assessment. Pharmacodynamic markers in PDXs were characterized by IHC and reverse-phase protein array.
Results:
Among several ERBB2-amplified cancers, CCNE1 co-amplification was identified (gastric 37%, endometroid 43%, and ovarian serous adenocarcinoma 41%). We hypothesized that adavosertib may enhance activity of HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd). In vitro, sensitivity to T-DXd was decreased by cyclin E overexpression and increased by knockdown, and adavosertib was synergistic with topoisomerase I inhibitor DXd. In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX models and prolonged event-free survival (EFS) in a HER2-overexpressing gastroesophageal cancer model. T-DXd + adavosertib treatment also increased EFS in other HER2-expressing tumor types, including a T-DXd-treated colon cancer model.
Conclusions:
We provide rationale for combining T-DXd with adavosertib in HER2-expressing cancers, especially with co-occuring CCNE1 amplifications. See related commentary by Rolfo et al., p. 4317.
Insights
Combining adavosertib with trastuzumab deruxtecan (T-DXd) shows promise for HER2-expressing cancers, particularly those with Cyclin E (CCNE1) amplification. This combination therapy demonstrated significant antitumor activity and improved event-free survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cyclin E (CCNE1) is implicated as a biomarker for adavosertib sensitivity and a resistance mechanism to HER2-targeted therapies.
- HER2-expressing cancers, including gastric, endometrioid, and ovarian serous adenocarcinomas, often exhibit ERBB2 amplification.
- Understanding the interplay between CCNE1 and HER2 signaling is crucial for developing effective combination therapies.
Purpose of the Study:
- To investigate the potential of combining adavosertib, a Wee1 kinase inhibitor, with trastuzumab deruxtecan (T-DXd), a HER2 antibody-drug conjugate.
- To evaluate the role of CCNE1 co-amplification in modulating sensitivity to HER2-targeted therapy and adavosertib.
- To assess the efficacy of the T-DXd + adavosertib combination in preclinical models of HER2-expressing cancers.
Main Methods:
- Analysis of The Cancer Genome Atlas and MD Anderson Cancer Center databases for ERBB2 and CCNE1 expression.
- In vitro studies involving CCNE1 overexpression or knockdown in HER2+ cell lines to assess drug combination efficacy.
- In vivo studies using patient-derived xenografts (PDX) in NSG mice treated with combinatorial therapy, followed by tumor growth and pharmacodynamic marker assessment.
Main Results:
- CCNE1 co-amplification was identified in a significant proportion of ERBB2-amplified cancers (gastric 37%, endometrioid 43%, ovarian serous adenocarcinoma 41%).
- In vitro, cyclin E overexpression decreased T-DXd sensitivity, while knockdown increased it; adavosertib showed synergy with DXd.
- In vivo, the T-DXd + adavosertib combination significantly enhanced antitumor activity and prolonged event-free survival in HER2-low, cyclin E-amplified gastroesophageal cancer PDX models and other HER2-expressing tumor types.
Conclusions:
- The study provides a strong rationale for combining T-DXd with adavosertib in HER2-expressing cancers, particularly those with concurrent CCNE1 amplifications.
- This combination strategy holds potential for overcoming resistance mechanisms and improving therapeutic outcomes in challenging cancer types.
- Further clinical investigation of this combination is warranted based on the promising preclinical data.
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