Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics

TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53-wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced cell death in TP53-mutant AML and stem/progenitor cells. The BH3 mimetic-driven stress response and cell death patterns after dual inhibition were largely independent of TP53 status and affected by apoptosis induction. Co-targeting, but not individual targeting of BCL-2 and MCL-1 in mice xenografted with TP53-WT and TP53-R248W Molm13 cells suppressed both TP53-WT and TP53-mutant cell growth and significantly prolonged survival. Our results demonstrate that co-targeting BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance to individual BH3 mimetics in TP53-mutant cells, thus shifting cell fate from survival to death in TP53-deficient and -mutant AML. This concept warrants clinical evaluation

Combined Inhibition of Bcl-2 and Mcl-1 Overcomes Bax Deficiency-Mediated Resistance of TP53-Mutant Acute Myeloid Leukemia to Individual BH3 Mimetics

TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53-wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced cell death in TP53-mutant AML and stem/progenitor cells. The BH3 mimetic-driven stress response and cell death patterns after dual inhibition were largely independent of TP53 status and affected by apoptosis induction. Co-targeting, but not individual targeting of BCL-2 and MCL-1 in mice xenografted with TP53-WT and TP53-R248W Molm13 cells suppressed both TP53-WT and TP53-mutant cell growth and significantly prolonged survival. Our results demonstrate that co-targeting BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance to individual BH3 mimetics in TP53-mutant cells, thus shifting cell fate from survival to death in TP53-deficient and -mutant AML. This concept warrants clinical evaluation

Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics

Abstract TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53–wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced cell death in TP53-mutant AML and stem/progenitor cells. The BH3 mimetic–driven stress response and cell death patterns after dual inhibition were largely independent of TP53 status and affected by apoptosis induction. Co-targeting, but not individual targeting of BCL-2 and MCL-1 in mice xenografted with TP53-WT and TP53-R248W Molm13 cells suppressed both TP53-WT and TP53-mutant cell growth and significantly prolonged survival. Our results demonstrate that co-targeting BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance to individual BH3 mimetics in TP53-mutant cells, thus shifting cell fate from survival to death in TP53-deficient and -mutant AML. This concept warrants clinical evaluation

Phase I/II Study of Trastuzumab in Combination With Everolimus (RAD001) in Patients With HER2-Overexpressing Metastatic Breast Cancer Who Progressed on Trastuzumab-Based Therapy

The audit industry is not any industry; it is crucial to all business activities. However, the trust of the auditors has been questioned following the noted corporate scandals which revealed financial crime and accounting fraud. Since the scandals affected large companies the most, and that large companies have auditing obligations, it is important to investigate how the trust of auditors appears in this group. The purpose of the study is therefore to explore factors that affect large firm's trust in auditors. The study is however limited to only investigate this nationally. Based on previous research, it can be assumed that the auditor's competence, independence, confidentiality and laws and norms affect the large companies’ trust. The four factors constitute the study's independent variables and thus the developed model. To empirically test the model, a web-based survey has been conducted, resulting in 78 answers. All independent variables proved to be positively significant, which means that there is a statistically positive connection between each independent variable and the dependent variable trust. The conclusion of the study is therefor that large companies have greater trust for an auditor who has good competence, acts independently, maintains the confidentiality and follow laws and norms of the audit industry. Since we investigated factors that affect large firm's trust, it would be interesting to read a comparative analysis of factors affecting the trust of small, medium and large companies. Another interesting study would be to investigate how the auditor agencies market to reach both existing and potential clients.Revisionsbranschen är inte vilken bransch som helst, den är nämligen avgörande för all näringsverksamhet. Däremot har förtroendet för revisorerna ifrågasatts efter de uppmärksammade företagsskandalerna som innebar att ekonomisk brottslighet och redovisningsfusk avslöjades. Då skandalerna berörde stora företag mest samt att stora företag har revisionsplikt, är det av betydelse att undersöka hur förtroendet för revisorerna ser ut i denna grupp. Studiens syfte är därför att utforska faktorer som påverkar stora företags förtroende för revisorer. Dock avgränsas studien till att enbart undersöka förtroendet för revisorer nationellt. Utifrån tidigare forskning kan det antas att revisorns kompetens, oberoende, tystnadsplikt samt lagar och normer påverkar de stora företagens förtroende. De fyra faktorerna utgör således studiens oberoende variabler och därmed utvecklade modell. För att empiriskt testa modellen har en webbaserad enkätundersökning genomförts, vilket resulterade i 78 fullständiga svar. Samtliga oberoende variabler visade sig vara positivt signifikanta, vilket tyder på att det finns ett statistiskt positivt samband mellan varje oberoende variabel och den beroende variabeln förtroende. Studiens slutsats är således att stora företag har högre förtroende för en revisor som har god kompetens, agerar oberoende, upprätthåller tystnadsplikten samt följer revisionsbranschens lagar och normer. Då vi undersökt faktorer som påverkar stora företags förtroende, hade det varit intressant att läsa en jämförande analys gällande faktorer som påverkar små, medelstora och stora företags förtroende. En annan intressant studie hade varit en undersökning om hur revisionsbyråer marknadsför sig för att nå både befintliga och potentiella klienter