A loss-of-function genetic screening identifies novel mediators of thyroid cancer cell viability

Maria Carmela Cantisani1, Alessia Parascandolo2, Merja Perälä3,4

  • 1IRCCS SDN, Naples, Italy.

Oncotarget
|April 9, 2016
PubMed

Insights

Researchers screened thyroid cancer cells for essential kinases, identifying 14 novel targets. These kinases are crucial for cancer cell survival but not normal cells, offering potential new therapeutic strategies for thyroid cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Protein kinases like RET and BRAF are key in thyroid cancer development.
  • Identifying novel kinases is crucial for developing targeted therapies.
  • Thyroid carcinoma exhibits complex molecular alterations driving its progression.

Purpose of the Study:

  • To identify novel kinases essential for thyroid carcinoma cell viability and proliferation.
  • To screen the human kinome for potential therapeutic targets in thyroid cancer.
  • To assess the specificity of identified kinases in cancer versus normal thyroid cells.

Main Methods:

  • RNA interference (siRNA) screening was performed on the TPC1 papillary thyroid cancer cell line.
  • A library of synthetic siRNAs targeting the human kinome was utilized.
  • Cell viability and proliferation were measured after silencing identified kinases.

Main Results:

  • 14 kinases were identified whose silencing significantly reduced thyroid cancer cell viability and proliferation.
  • These kinases showed activity across various thyroid cancer subtypes, including papillary and anaplastic carcinomas with different mutations (RET, BRAF, RAS).
  • Silencing of these kinases did not significantly impact normal thyroid cells (NTHY), indicating cancer-specific effects.

Conclusions:

  • The identified kinases represent potential novel, druggable targets for thyroid cancer therapy.
  • The specificity for cancer cells suggests a favorable therapeutic window.
  • Further exploration of these EPH receptor, SRC, and MAPK family members is warranted for drug development.

Related Concept Videos

Genetic Screens02:46

Genetic Screens

Genetic screens are tools used to identify genes and mutations responsible for phenotypes of interest. Genetic screens help identify individuals or a group of people at risk of developing  genetic diseases and help them with early intervention, targeted therapy, and reproductive options.
Forward genetic screens
Forward or “classical” genetic screens involve creating random mutations in an organism’s DNA using radiation, mutagens, or insertion of additional bases, which...
5.9K
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
6.2K
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

2.0K
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
10.0K
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

2.9K
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
65