Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

Yan, Gonghong; Wang, Heping; Luna, Augustin; Bozorgui, Behnaz; Li, Xubin; Sanchez, Maga; Dereli, Zeynep; Kahraman, Nermin; Kara, Göknur; Chen, Xiaohua; Lu, Yiling; Babur, Özgün; Çokol, Murat; Özpolat, Bülent; Sander, Chris; Mills, Gordon B.; Korkut, Anil

doi:10.1101/711895

Cited by 6 publications

(8 citation statements)

References 63 publications

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“…The network-level adaptive responses were computed using the Target Score algorithm as described in Yan and colleagues (30). The method is developed on the rationale that collective molecular responses of functionally associated molecule have a higher likelihood of therapeutic relevance than changes in abundances of individual molecules.…”

Section: Rppa Analysismentioning

confidence: 99%

“…We further analyzed adaptive responses with the Target Score algorithm, which quantifies network modules of functionally related molecular entities involved in adaptive responses to targeted perturbations (30). Using the Target Score algorithm, we analyzed the network-level adaptive responses to neratinib, palbociclib, everolimus, and trametinib (Fig.…”

Section: Effects Of Neratinib Combination On Functional Proteomics Of Her2 þ Pdxsmentioning

confidence: 99%

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Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Zhao

Scott

Evans

et al. 2021

Clinical Cancer Research

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Purpose: Neratinib is an irreversible, pan-HER tyrosine kinase inhibitor that is FDA approved for HER2-overexpressing/amplified (HER2 þ ) breast cancer. In this preclinical study, we explored the efficacy of neratinib in combination with inhibitors of downstream signaling in HER2 þ cancers in vitro and in vivo.Experimental Design: Cell viability, colony formation assays, and Western blotting were used to determine the effect of neratinib in vitro. In vivo efficacy was assessed with patient-derived xenografts (PDX): two breast, two colorectal, and one esophageal cancer (with HER2 mutations). Four PDXs were derived from patients who received previous HER2-targeted therapy. Proteomics were assessed through reverse phase protein arrays and network-level adaptive responses were assessed through Target Score algorithm.Results: In HER2 þ breast cancer cells, neratinib was synergistic with multiple agents, including mTOR inhibitors ever-olimus and sapanisertib, MEK inhibitor trametinib, CDK4/6 inhibitor palbociclib, and PI3Ka inhibitor alpelisib. We tested efficacy of neratinib with everolimus, trametinib, or palbociclib in five HER2 þ PDXs. Neratinib combined with everolimus or trametinib led to a 100% increase in median event-free survival (EFS; tumor doubling time) in 25% (1/4) and 60% (3/5) of models, respectively, while neratinib with palbociclib increased EFS in all five models. Network analysis of adaptive responses demonstrated upregulation of EGFR and HER2 signaling in response to CDK4/6, mTOR, and MEK inhibition, possibly providing an explanation for the observed synergies with neratinib.Conclusions: Taken together, our results provide strong preclinical evidence for combining neratinib with CDK4/6, mTOR, and MEK inhibitors for the treatment of HER2 þ cancer.

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Section: Rppa Analysismentioning

confidence: 99%

Section: Effects Of Neratinib Combination On Functional Proteomics Of Her2 þ Pdxsmentioning

confidence: 99%

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Zhao

Scott

Evans

et al. 2021

Clinical Cancer Research

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“…Compared to the MCL1 inhibitor, the BCL2 inhibitor had a limited impact on growth rate as well as viability (Figure S5). The relatively limited efficacy of targeting BCL2 is expected as drug naïve HCC1954 cells are copy number-amplified for the MCL1 gene and have higher baseline MCL1 protein expression, resulting in a potential dependence on the anti-apoptotic activity of MCL1 (53,71).…”

Section: Figure 5 Rational Combination Therapies From Targetscore Analysis Growth Rate Changes In Response To Combinations Of Parp Shp2 Amentioning

confidence: 99%

Targeting Adaptation to Cancer Treatment by Drug Combinations

Wang

Luna

Yan

et al. 2021

Preprint

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Adaptation of tumors to therapeutic interventions contributes to dismal long-term patient outcomes. Adaptation to therapy involves co-action of functionally related proteins that together activate cell survival programs and compensate for the therapeutic impact. Oncogenic dependencies to such adaptive events, however, can generate new therapeutic vulnerabilities that can be targeted with drug combinations. The precision medicine approaches in which targeted drugs are matched to pre-existing genomic aberrations fail to address the adaptive responses and resulting vulnerabilities. Here, we provide the mathematical formulation, implementation and validation of the TargetScore method. The TargetScore identifies collective adaptive responses to targeted interventions as concurrent changes of phospho-proteins that are connected within a signaling network. Based on the adaptive responses, the method predicts drug-induced vulnerabilities. Using TargetScore, we inferred the adaptive responses with short-term (i.e., days) stress and long-term (i.e., months) acquired resistance to inhibitors of anti-apoptotic mediators, MCL1 and BCL2. With experiments guided by the predictions, we identified synergistic interactions between inhibitors of PARP, SHP2, and MCL1 in breast cancer cells. TargetScore is readily applicable to existing precision oncology efforts by matching targeted drug combinations to emerging molecular signatures under therapeutic stress.

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“…Analysis of membrane uidity was performed as described previously 56 with slight modi cations. Brie y, 293FT/ACE2/TMPRSS2/DSP1-7 cells in 24-well plates were treated with the indicated concentrations of the compounds for 2 days.…”

Section: Analysis Of Cellular Membrane Uiditymentioning

confidence: 99%

N-(4-Hydroxyphenyl)retinamide suppresses SARS-CoV-2 spike protein-mediated cell-cell fusion and viral infection in vitro 

Hayashi

Tsuchiya

Yamamoto

et al. 2021

Preprint

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The coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), persists worldwide with limited therapeutic options. Since membrane fusion between SARS-CoV-2 and host cells is essential for the early step of the infection, the membrane compositions, including sphingolipids, in host cells are considered to affect the viral infection. However, the role of sphingolipids in the life cycle of SARS-CoV-2 remains unclear. Here, we assessed several inhibitors of sphingolipid metabolism enzymes against SARS-CoV-2 spike protein-mediated cell-cell fusion and viral infection in vitro. Among the compounds tested, only N-(4-hydroxyphenyl)retinamide (4-HPR, also known as fenretinide), an inhibitor of dihydroceramide Δ4-desaturase 1 (DES1) and well known for having antitumour activity, suppressed cell-cell fusion (50% effective concentration [EC50] = 4.1 mM) and viral infection ([EC50] = 4.4 mM), wherein the EC50 values are below its plasma concentration in previous clinical trials on tumours. DES1 catalyses the introduction of a double bond in dihydroceramide, and the inhibition efficiencies observed were consistent with an increased ratio of saturated sphinganine-based lipids to total sphingolipids and the decreased cellular membrane fluidity. These findings, together with the accumulated clinical data regarding the safety of 4-HPR, make it a likely candidate drug to treat COVID-19.

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Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

Cited by 6 publications

References 63 publications

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Targeting Adaptation to Cancer Treatment by Drug Combinations

N-(4-Hydroxyphenyl)retinamide suppresses SARS-CoV-2 spike protein-mediated cell-cell fusion and viral infection in vitro

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Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

Cited by 6 publications

References 63 publications

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer

Targeting Adaptation to Cancer Treatment by Drug Combinations

N-(4-Hydroxyphenyl)retinamide suppresses SARS-CoV-2 spike protein-mediated cell-cell fusion and viral infection in vitro&nbsp;

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N-(4-Hydroxyphenyl)retinamide suppresses SARS-CoV-2 spike protein-mediated cell-cell fusion and viral infection in vitro