A combinatorial drug screen in PDX-derived primary rhabdomyosarcoma cells identifies the NOXA - BCL-XL/MCL-1 balance as target for re-sensitization to first-line therapy in recurrent tumors.

Published on Jul 27, 2021in Neoplasia5.696
· DOI :10.1016/J.NEO.2021.07.001
Gabriele Manzella3
Estimated H-index: 3
(Boston Children's Hospital),
Devmini C Moonamale (Boston Children's Hospital)+ 3 AuthorsBeat W. Schäfer71
Estimated H-index: 71
(Boston Children's Hospital)
First-line therapy for most pediatric sarcoma is based on chemotherapy in combination with radiotherapy and surgery. A significant number of patients experience drug resistance and development of relapsed tumors. Drugs that have the potential to re-sensitize relapsed tumor cells toward chemotherapy treatment are therefore of great clinical interest. Here, we used a drug profiling platform with PDX-derived primary rhabdomyosarcoma cells to screen a large drug library for compounds re-sensitizing relapse tumor cells toward standard chemotherapeutics used in rhabdomyosarcoma therapy. We identified ABT-263 (navitoclax) as most potent compound enhancing general chemosensitivity and used different pharmacologic and genetic approaches in vitro and in vivo to detect the NOXA-BCL-XL/MCL-1 balance to be involved in modulating drug response. Our data therefore suggests that players of the intrinsic mitochondrial apoptotic cascade are major targets for stimulation of response toward first-line therapies in rhabdomyosarcoma.
📖 Papers frequently viewed together
10 Authors (Clara Alcon, ..., Joan Montero)
#1Gabriele Manzella (Boston Children's Hospital)H-Index: 3
#2Leonie D Schreck (Boston Children's Hospital)H-Index: 1
Last. Marco Wachtel (Boston Children's Hospital)H-Index: 13
view all 18 authors...
Cancer therapy is currently shifting from broadly used cytotoxic drugs to patient-specific precision therapies. Druggable driver oncogenes, identified by molecular analyses, are present in only a subset of patients. Functional profiling of primary tumor cells could circumvent these limitations, but suitable platforms are unavailable for most cancer entities. Here, we describe an in vitro drug profiling platform for rhabdomyosarcoma (RMS), using a living biobank composed of twenty RMS patient-der...
#1Clara AlconH-Index: 1
Last. Joan MonteroH-Index: 21
view all 11 authors...
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis that combined with the lack of specific biomarkers impairs the development of new therapies. Here, we utilize dynamic BH3 profiling (DBP), a functional predictive biomarker that measures net changes in mitochondrial apoptotic signaling, to identify anti-apoptotic adaptations upon treatment. We employ this information to guide the use of BH3 mimetics...
#1Johannes Ommer (Boston Children's Hospital)H-Index: 1
#2Joanna SelfeH-Index: 11
Last. Beat W. Schäfer (Boston Children's Hospital)H-Index: 71
view all 13 authors...
The clinically aggressive alveolar rhabdomyosarcoma subtype is characterized by expression of the oncogenic fusion protein PAX3-FOXO1, which is critical for tumorigenesis and cell survival. Here we studied the mechanism of cell death induced by loss of PAX3-FOXO1 expression and identified a novel pharmacological combination therapy that interferes with PAX3-FOXO1 biology at different levels. Depletion of PAX3-FOXO1 in fusion positive (FP)-RMS cells induced intrinsic apoptosis in a NOXA-dependent...
#1Sajid Khan (UF: University of Florida)
B-cell lymphoma extra large (BCL-XL) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and can...
#1Erinna F. Lee (La Trobe University)H-Index: 33
#2Tiffany J HarrisH-Index: 3
Last. W. Douglas Fairlie (La Trobe University)H-Index: 36
view all 20 authors...
Malignant melanoma is one of the most difficult cancers to treat due to its resistance to chemotherapy. Despite recent successes with BRAF inhibitors and immune checkpoint inhibitors, many patients do not respond or become resistant to these drugs. Hence, alternative treatments are still required. Due to the importance of the BCL-2-regulated apoptosis pathway in cancer development and drug resistance, it is of interest to establish which proteins are most important for melanoma cell survival, th...
#1Delphine MerinoH-Index: 22
#2Gemma L. Kelly (University of Melbourne)H-Index: 25
Last. Andreas Strasser (University of Melbourne)H-Index: 134
view all 6 authors...
Defects in apoptotic cell death can promote cancer and impair responses of malignant cells to anti-cancer therapy. Pro-survival BCL-2 proteins prevent apoptosis by keeping the cell death effectors, BAX and BAK, in check. The BH3-only proteins initiate apoptosis by neutralizing the pro-survival BCL-2 proteins. Structural analysis and medicinal chemistry led to the development of small-molecule drugs that mimic the function of the BH3-only proteins to kill cancer cells. The BCL-2 inhibitor venetoc...
#1Ryan S. Soderquist (Duke University)H-Index: 6
#2Lorin Crawford (Brown University)H-Index: 11
Last. Kris C. Wood (Duke University)H-Index: 24
view all 10 authors...
While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly understood. Here we develop a drug screening approach to define the sensitivity of cancer cells from ten tissue types to all possible combinations of selective BCL-2, BCL-XL, and MCL-1 inhibitors and discover that most cell lines depend on at least one combination for survival. We demonstrate that expression...
#1Uri Ben-David (Broad Institute)H-Index: 27
#2Benjamin Siranosian (Broad Institute)H-Index: 6
Last. Todd R. GolubH-Index: 162
view all 30 authors...
Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Sim...
#1Jarno DrostH-Index: 22
#2Hans Clevers (KNAW: Royal Netherlands Academy of Arts and Sciences)H-Index: 205
The recent advances in in vitro 3D culture technologies, such as organoids, have opened new avenues for the development of novel, more physiological human cancer models. Such preclinical models are essential for more efficient translation of basic cancer research into novel treatment regimens for patients with cancer. Wild-type organoids can be grown from embryonic and adult stem cells and display self-organizing capacities, phenocopying essential aspects of the organs they are derived from. Gen...
#1Clare E. Weeden (University of Melbourne)H-Index: 6
#2Casey Ah-Cann (University of Melbourne)H-Index: 5
Last. Marie Liesse Asselin-Labat (University of Melbourne)H-Index: 27
view all 8 authors...
Genetic alterations in the fibroblast growth factor receptors (FGFRs) have been described in multiple solid tumours including bladder cancer, head and neck and lung squamous cell carcinoma (SqCC). However, recent clinical trials showed limited efficacy of FGFR-targeted therapy in lung SqCC, suggesting combination therapy may be necessary to improve patient outcomes. Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We ...
Cited By0
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.