A5046439857- Pancreatic and Hepatic Oncology Research
- Genomics and Rare Diseases
- Melanoma and MAPK Pathways
- PI3K/AKT/mTOR signaling in cancer
- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- Synthesis and biological activity
- CRISPR and Genetic Engineering
- Advanced Breast Cancer Therapies
- TGF-β signaling in diseases
- Synthesis of Tetrazole Derivatives
- PARP inhibition in cancer therapy
- Cancer Research and Treatments
- Diabetes Treatment and Management
- Colorectal Cancer Treatments and Studies
- Chromatin Remodeling and Cancer
- Renal cell carcinoma treatment
- Health and Medical Research Impacts
- Infectious Diseases and Mycology
- Biomedical Ethics and Regulation
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Colorectal Cancer Surgical Treatments
- Genomics and Chromatin Dynamics
- Fungal Plant Pathogen Control
Sanofi (France)
2019-2023
The TGFβ signaling mediator SMAD4 is frequently mutated or deleted in colorectal and pancreatic cancers. acts as a tumor suppressor its loss associated with poorer patient outcomes. purpose of this study was to find synthetic lethal interactions deficiency novel therapeutic strategies for the treatment patients SMAD4-deficient Using pooled lentiviral single-guide RNA libraries, we conducted genome-wide loss-of-function screens Cas9-expressing cancer cells harboring altered wild-type SMAD4....
<div>Abstract<p>The introduction of MAPK pathway inhibitors paved the road for significant advancements in treatment <i>BRAF</i>-mutant (<i>BRAF</i><sup>MUT</sup>) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative option, most likely because these pathways constitute codependent signaling network. Concomitant <i>PTEN</i> loss function (<i>PTEN</i><sup>LOF</sup>)...
<div>Abstract<p>The introduction of MAPK pathway inhibitors paved the road for significant advancements in treatment <i>BRAF</i>-mutant (<i>BRAF</i><sup>MUT</sup>) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative option, most likely because these pathways constitute codependent signaling network. Concomitant <i>PTEN</i> loss function (<i>PTEN</i><sup>LOF</sup>)...
<p>Supplementary materials and methods.</p>
<p>A) <i>PTEN<sup>LOF</sup></i>/<i>BRAF<sup>MUT</sup></i> melanoma lines were treated with serial dilutions of the indicated drugs and their effect on phosphorylated total Akt was evaluated by RPPA. B) <i>PTEN<sup>LOF</sup></i> calls in CCLE translate into absence PTEN protein as immunoblotting a panel <i>BRAF<sup>MUT</sup></i> using antibodies targeting amino- carboxy-terminus PTEN....
<p>Despite major dependence of <i>PTEN<sup>LOF</sup></i>/<i>BRAF<sup>MUT</sup></i> melanoma cell lines on PI3Kβ, PI3Kαi synergizes with PI3Kβi to inhibit downstream signaling upon long-term treatment. A) +B) Effects treatment the indicated inhibitors as single-agents or in combination for 2h (A) and 72h (B) PI3K was determined by immunoblotting lines. PI3Kβi=rac-KIN-193, PI3Kαi=BYL719, PI3Kδi=CAL101</p>
<p>Supplementary figure legends.</p>
<p>IGF1R inhibition synergizes with PI3Kβ in WM-266-4, but not A-375. A) Synergistic proliferation upon PI3K/IGF1R inhibitor combination WM-266-4 cells. cells were treated increasing concentrations of PI3Ki and IGF1Ri as single-agents or a fixed concentration 1.1μM IGF1Ri. The data shown represents the mean ({plus minus}SEM) two replicates. B) + C) Determination synergy (B) A-375 (C) using assays. Dose matrices highlight percentages relative to DMSO 100 indicating complete block...
<p>Cartoon illustrating the requirement of concomitant inhibition PI3Kβ together with PI3Kα or IGF1R and MAPK signaling to achieve complete long-term pathway in <i>PTEN<sup>LOF</sup></i>/<i>BRAF<sup>MUT</sup></i> melanoma.</p>
<p>PI3Kβ inhibition induces p85/IRS2 interaction in a time-dependent manner the <i>PTEN<sup>LOF</sup></i>/<i>BRAF<sup>MUT</sup></i> melanoma cell line RVH-421 that is mediated by negative feedback signaling. A) Co-immunoprecipitation experiments were carried out using lysates of treated with PI3Kbi for indicated time and blotted p85, pTyr (IRS2). B)-D) Input immunoprecipitation shown Figure 4 immunoblotted phospho-specific or total target...
<p>Concomitant inhibition of PI3Kβ, IGF1R and MAPK signaling are leading to full long-term pathway blockade. A) +B) Effects treatment with the indicated inhibitors as single-agents or in combination on WM-266-4 (A) RVH-421 (B) were evaluated by immunoblotting using phospho-specific total target protein antibodies. PI3Kβi=rac-KIN-193, PI3Kαi=BYL719, IGF1Ri (A)=AEW541, (B)=Figitumumab-like antibody, MEKi=MEK162</p>
<p>Concomitant inhibition of PI3Kβ, IGF1R and MAPK signaling are leading to induction cell death. A) Effects treatment with the indicated inhibitors as single-agents in RVH-421 were evaluated by immunoblotting using phospho-specific or total target protein antibodies. B) Fractions living (A-/PI-), necrotic (A-/PI+), early (A+/PI-) late (A+/PI+) apoptotic cells was measured upon A101D C32 compounds for 72h. Data represented mean ({plus minus}SD) triplicates. PI3Kβi=rac-KIN-193,...
<p>MAPK pathway inhibition synergizes with PI3Kβ in WM-266-4, but not A-375. A-D) Determination of PI3K/BRAF and PI3K/MEK inhibitor synergy WM-266-4 (A+B) A-375 (C+D) using proliferation assays. Dose matrices highlight percentages relative to DMSO 100 indicating complete block >100 indicative cell death. SS, score. PI3Kβi1/2=rac-KIN-193/GSK-2636771, panPI3Ki=GDC0941, PI3Kαi=BYL719, BRAFi=LGX818, MEKi=MEK162</p>
<p>PI3K pathway inhibition using PI3Kβi/PI3Kαi or PI3Kβi/IGF1Ri enhances the anti-proliferative effect of BRAF/MEK regimen in <i>PTEN<sup>LOF</sup></i>/<i>BRAF<sup>MUT</sup></i> cell lines and shifts response towards death A+B) Validation BRAFi/MEKi activity RVH-421 (A) WM-266-4 (B) absence presence proliferation (upper panels; growth matrix highlighting percentages relative to DMSO) assays (lower fraction PI-positive, dead cells)....
<p>Concomitant inhibition of PI3Kβ, IGF1R and MAPK signaling are leading to induction cell death. A) Effects treatment with the indicated inhibitors as single-agents in RVH-421 were evaluated by immunoblotting using phospho-specific or total target protein antibodies. B) Fractions living (A-/PI-), necrotic (A-/PI+), early (A+/PI-) late (A+/PI+) apoptotic cells was measured upon A101D C32 compounds for 72h. Data represented mean ({plus minus}SD) triplicates. PI3Kβi=rac-KIN-193,...
<p>Supplementary figure legends.</p>
<p>Supplementary materials and methods.</p>
<p>PI3K pathway inhibition using PI3Kβi/PI3Kαi or PI3Kβi/IGF1Ri enhances the anti-proliferative effect of BRAF/MEK regimen in <i>PTEN<sup>LOF</sup></i>/<i>BRAF<sup>MUT</sup></i> cell lines and shifts response towards death A+B) Validation BRAFi/MEKi activity RVH-421 (A) WM-266-4 (B) absence presence proliferation (upper panels; growth matrix highlighting percentages relative to DMSO) assays (lower fraction PI-positive, dead cells)....
<p>Cartoon illustrating the requirement of concomitant inhibition PI3Kβ together with PI3Kα or IGF1R and MAPK signaling to achieve complete long-term pathway in <i>PTEN<sup>LOF</sup></i>/<i>BRAF<sup>MUT</sup></i> melanoma.</p>
<p>Despite major dependence of <i>PTEN<sup>LOF</sup></i>/<i>BRAF<sup>MUT</sup></i> melanoma cell lines on PI3Kβ, PI3Kαi synergizes with PI3Kβi to inhibit downstream signaling upon long-term treatment. A) +B) Effects treatment the indicated inhibitors as single-agents or in combination for 2h (A) and 72h (B) PI3K was determined by immunoblotting lines. PI3Kβi=rac-KIN-193, PI3Kαi=BYL719, PI3Kδi=CAL101</p>
<p>IGF1R inhibition synergizes with PI3Kβ in WM-266-4, but not A-375. A) Synergistic proliferation upon PI3K/IGF1R inhibitor combination WM-266-4 cells. cells were treated increasing concentrations of PI3Ki and IGF1Ri as single-agents or a fixed concentration 1.1μM IGF1Ri. The data shown represents the mean ({plus minus}SEM) two replicates. B) + C) Determination synergy (B) A-375 (C) using assays. Dose matrices highlight percentages relative to DMSO 100 indicating complete block...