SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance

Randazzo, Ornella; Cascioferro, Stella; Pecoraro, Camilla; Iddouch, Widad Ait; Avan, Amir; Parrino, Barbara; Carbone, Daniela; Perricone, Ugo; Peters, Godefridus J.; Diana, Patrizia; Giovannetti, Elisa

doi:10.20517/cdr.2021.61

Cited by 2 publications

(4 citation statements)

References 82 publications

(217 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also observed mutations in other genes reported to be sensitive to inhibitors in different cancer types, such as BRAF , SF3B1 , ATM , KRAS , PIK3C2G , and KMT2A . 31 Moreover, the RET mutation–negative MTC cohort also showed elevated accumulation of mutations in the transcriptional misregulation pathway of cancer, opening a possibility to further study transcriptional addiction in rare cancer 32,33 and its therapeutic application. 34…”

Section: Discussionmentioning

confidence: 99%

RET Alterations Differentiate Molecular Profile of Medullary Thyroid Cancer

Prabhash,

Saldanha,

Patil

et al. 2024

JCO Precis Oncol

View full text Add to dashboard Cite

PURPOSE Medullary thyroid cancer (MTC) is a rare cancer originating from parafollicular C cells of the thyroid gland. Therapeutically relevant alterations in MTC are predominantly reported in RET oncogene, and lower-frequency alterations are reported in KRAS and BRAF. Nevertheless, there is an unmet need existing to analyze the MTC in the Indian cohort by using in-depth sequencing techniques that go beyond the identification of known therapeutic biomarkers. MATERIALS AND METHODS Here, we characterize MTC using integrative whole-exome and whole-transcriptome sequencing of 32 MTC tissue samples. We performed clinically relevant variant analysis, molecular pathway analysis, tumor immune-microenvironment analysis, and structural characterization of RET novel mutation. RESULTS Mutational landscape analysis shows expected RET mutations in 50% of the cases. Furthermore, we observed mutations in known cancer genes like KRAS, HRAS, SF3B1, and BRAF to be altered only in the RET-negative cohort. Pathway analysis showed differential enrichment of mutations in transcriptional deregulation genes in the RET-negative cohort. Furthermore, we observed novel RET kinase domain mutation Y900S showing affinity to RET inhibitors accessed via molecular docking and molecular dynamics simulation. CONCLUSION Altogether, this study provides a detailed genomic characterization of patients with MTC of Indian origin, highlighting the possible utility of targeted therapies in this disease.

show abstract

Section: Discussionmentioning

confidence: 99%

RET Alterations Differentiate Molecular Profile of Medullary Thyroid Cancer

Prabhash,

Saldanha,

Patil

et al. 2024

JCO Precis Oncol

View full text Add to dashboard Cite

show abstract

“…Underlying the fully fledged mechanism of chemotherapy resistance is very intricate in cancer, given that many determining factors may be involved. Essentially, both innate and adaptive mechanisms can concurrently lead to the PDAC-resistant phenotype [9] . Analogously, native and acquired alterations in either nucleoside transporters or metabolic enzymes may prompt PDAC cells to gemcitabine resistance [10] .…”

Section: Introductionmentioning

confidence: 99%

“…Secreting soluble factors, remodeling extracellular matrix, delivering exosomes, reprogramming the metabolic process, and the epigenetic landscape of tumor cells are some of the stromarelated properties leading to resistance [27,28] . In addition, there is an ever-growing awareness of the crucial role driven by cancer cell metabolism in influencing drug response [9,29] . In accordance with this perspective, targeting precise metabolic pathways, which include, among others, glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) [30][31][32] , has recently been recognized as a promising pharmacological approach to overcome chemoresistance in PDAC.…”

Section: Introductionmentioning

confidence: 99%

“…Essentially, both innate and adaptive mechanisms can concurrently lead to the PDAC-resistant phenotype [ 9 ] . Analogously, native and acquired alterations in either nucleoside transporters or metabolic enzymes may prompt PDAC cells to gemcitabine resistance [ 10 ] . Due to its hydrophilicity, cellular uptake is mediated by human equilibrative nucleoside transporters (hENTs) and human concentrative nucleoside transporters (hCNTs), although hENT1 accounts for transporting almost the entire amount of gemcitabine into cytosol [ 11 ] .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

AdipoRon and Pancreatic Ductal Adenocarcinoma: a future perspective in overcoming chemotherapy-induced resistance?

et al. 2022

View full text Add to dashboard Cite

The latest scientific knowledge has provided additional insights accountable for the worst prognosis for pancreatic ductal adenocarcinoma (PDAC). Among the causative factors, the aptitude to develop resistance towards approved medications denotes the master key for understanding the lack of improvement in PDAC survival over the years. Even though several compounds have achieved encouraging results at preclinical stage, no new adjuvant agents have reached the bedside of PDAC patients lately. The adiponectin receptor agonist AdipoRon is emerging as a promising anticancer drug in different cancer models, particularly in PDAC. Building on the existing findings, we recently reinforced its candidacy in PDAC cells, proposing AdipoRon either as a suitable partner in gemcitabine-based treatment or as an effective drug in resistant cells. Crossing the current state-of-the-art, herein we provide a critical perspective on AdipoRon to figure out whether this receptor agonist can potentially be considered a future therapeutic choice in overcoming chemotherapy-induced resistance, expressly in PDAC.

show abstract

SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance

Abstract: Aim: Because mutations of splicing factor 3B subunit-1 (SF3B1) have been identified in 4% of pancreatic ductal adenocarcinoma (PDAC) patients, we investigated the activity of new potential inhibitors of SF3B1 in combination with gemcitabine, one of the standard drugs, in PDAC cell lines.

Cited by 2 publications

References 82 publications

RET Alterations Differentiate Molecular Profile of Medullary Thyroid Cancer

RET Alterations Differentiate Molecular Profile of Medullary Thyroid Cancer

AdipoRon and Pancreatic Ductal Adenocarcinoma: a future perspective in overcoming chemotherapy-induced resistance?

Contact Info

Product

Resources

About