Related Experiment Video

Updated: Jun 14, 2025

Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
07:16

Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor

Published on: September 13, 2018

19.7K

Transposon mediated functional genomic screening for BRAF inhibitor resistance reveals convergent Hippo and MAPK

Li Chen1, Iulian Pruteanu-Malinici2,3, Anahita Dastur2,4

  • 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA. lichenboston@gmail.com.

Scientific Reports
|January 24, 2025
PubMed

Insights

Targeted melanoma therapies like BRAF inhibitors face drug resistance. This study identified key resistance genes and mechanisms, including the Hippo pathway, offering potential strategies to overcome treatment hurdles.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • BRAF inhibitors are effective against BRAF-mutant melanoma but drug resistance limits their success.
  • Identifying mechanisms of resistance is crucial for improving targeted cancer therapies.

Purpose of the Study:

  • To identify genes conferring resistance to BRAF inhibition in melanoma using a piggyBac transposon activation mutagenesis screen.
  • To elucidate the functional diversity of resistance mechanisms and identify key pathways involved.

Main Methods:

  • Utilized a piggyBac transposon activation mutagenesis screen in melanoma to identify resistance genes.
  • Performed integrative analysis of resistance genes to determine functional diversity.
  • Investigated the role of the Hippo pathway effector TAZ in mediating resistance.

Main Results:

  • Identified genes conferring resistance to BRAF inhibition.
  • Revealed that resistance mechanisms converge on a limited number of pathways, including MAPK, PI3K-AKT, and Hippo pathways.
  • Demonstrated TAZ's critical role in BRAF inhibition resistance via transcriptional regulation and interaction with NEDD4L.

Conclusions:

  • A limited set of therapeutic strategies may overcome resistance mediated by a large gene set.
  • The Hippo pathway, particularly TAZ, is a key mediator of BRAF inhibition resistance in melanoma.
  • Targeting TAZ and associated pathways could offer new therapeutic avenues for BRAF-mutant melanoma.
Keywords:
BRAF inhibitor resistanceHippo pathwayNEDD4LTAZTransposon mutagenesis screen

More Related Videos

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter11:32

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

Published on: March 27, 2020

6.9K
A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells10:13

A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells

Published on: July 3, 2013

11.1K

Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.3K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.4K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.2K