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Network-informed discovery of multidrug combinations for ERα+/HER2-/PI3Kα-mutant breast cancer
Dina Hany1,2, Marloes Zoetemelk3,4,5, Kaushik Bhattacharya1
1Département de Biologie Moléculaire et Cellulaire, Université de Genève, Sciences III, Quai Ernest-Ansermet 30, 1211, Genève 4, Switzerland.
Abstract:
Breast cancer is a persistent threat to women worldwide. A large proportion of breast cancers are dependent on the estrogen receptor α (ERα) for tumor progression. Therefore, targeting ERα with antagonists, such as tamoxifen, or estrogen deprivation by aromatase inhibitors remain standard therapies for ERα + breast cancer. The clinical benefits of monotherapy are often counterbalanced by off-target toxicity and development of resistance. Combinations of more than two drugs might be of great therapeutic value to prevent resistance, and to reduce doses, and hence, decrease toxicity. We mined data from the literature and public repositories to construct a network of potential drug targets for synergistic multidrug combinations. With 9 drugs, we performed a phenotypic combinatorial screen with ERα + breast cancer cell lines. We identified two optimized low-dose combinations of 3 and 4 drugs of high therapeutic relevance to the frequent ERα + /HER2-/PI3Kα-mutant subtype of breast cancer. The 3-drug combination targets ERα in combination with PI3Kα and cyclin-dependent kinase inhibitor 1 (p21). In addition, the 4-drug combination contains an inhibitor for poly (ADP-ribose) polymerase 1 (PARP1), which showed benefits in long-term treatments. Moreover, we validated the efficacy of the combinations in tamoxifen-resistant cell lines, patient-derived organoids, and xenograft experiments. Thus, we propose multidrug combinations that have the potential to overcome the standard issues of current monotherapies.
Insights
New multidrug combinations show promise for treating estrogen receptor-positive (ERα+) breast cancer. These low-dose therapies target key pathways, potentially overcoming resistance and reducing toxicity associated with current treatments.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Estrogen receptor alpha (ERα)-positive breast cancer is a significant global health concern.
- Current therapies like tamoxifen and aromatase inhibitors target ERα but face challenges of resistance and toxicity.
- Multidrug combinations may offer enhanced efficacy and reduced side effects compared to monotherapy.
Purpose of the Study:
- To identify synergistic multidrug combinations for ERα-positive breast cancer treatment.
- To develop low-dose combination therapies effective against common breast cancer subtypes, including tamoxifen-resistant and PI3Kα-mutant variants.
- To evaluate the therapeutic potential of novel drug combinations in preclinical models.
Main Methods:
- Literature and database mining to construct a drug target network.
- Phenotypic combinatorial screening of 9 drugs in ERα-positive breast cancer cell lines.
- Validation of promising combinations in tamoxifen-resistant cell lines, patient-derived organoids, and xenograft models.
Main Results:
- Two optimized low-dose combinations (3 and 4 drugs) were identified.
- A 3-drug combination targets ERα, PI3Kα, and p21.
- A 4-drug combination includes a PARP1 inhibitor, showing long-term treatment benefits.
- Combinations demonstrated efficacy in tamoxifen-resistant models and patient-derived organoids.
Conclusions:
- Novel multidrug combinations offer a promising strategy to overcome limitations of current breast cancer monotherapies.
- Targeting ERα, PI3Kα, p21, and PARP1 concurrently may provide a more effective and less toxic treatment approach.
- These findings support the clinical translation of optimized multidrug regimens for ERα-positive breast cancer.
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