Related Experiment Video

Updated: May 18, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model

Hoi Yee Chow1, Adrian M Jubb, Jennifer N Koch

  • 1Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

Cancer Research
|September 18, 2012
PubMed

Insights

p21-activated kinase 1 (Pak1) is a promising target for Ras-driven cancers. Inhibiting Pak1 reduces tumor growth and impacts key cancer signaling pathways, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • RAS genes are frequently mutated in cancer, posing therapeutic challenges due to difficulties in directly targeting Ras proteins.
  • Downstream signaling pathways like Raf/Mek/Erk and PI3K/Akt/mTOR are crucial in Ras-driven tumors.
  • p21-activated kinase 1 (Pak1) regulates these pathways and is upregulated in various human cancers.

Purpose of the Study:

  • To investigate the role of Pak1 in Ras-driven skin cancer.
  • To determine if Pak1 is a viable therapeutic target in KRAS-driven tumors.

Main Methods:

  • Analysis of PAK1 expression in human squamous cell carcinoma (SCC) correlating with stage and grade.
  • Utilizing a mouse model of Kras-driven SCC to assess the impact of Pak1 gene deletion on tumorigenesis.
  • Administering small molecule Pak inhibitors (PF3758309, FRAX597), a Mek inhibitor, and an Akt inhibitor to Kras(G12D) mice.

Main Results:

  • A positive correlation was observed between advanced SCC stage/grade and PAK1 expression.
  • Pak1 gene deletion in mice significantly reduced SCC tumorigenesis and progression, with diminished Erk and Akt activity.
  • Pak1 inhibitor treatment led to tumor regression and reduced Erk/Akt activity in Kras(G12D) mice.
  • Mek inhibition also caused tumor regression, while Akt inhibition did not.

Conclusions:

  • Pak1 is a novel therapeutic target in KRAS-driven tumors.
  • Pak1 inhibition exerts its anti-tumor effects primarily through the Erk signaling pathway, not the Akt pathway.

More Related Videos

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate (DMBA-TPA)04:12

Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate (DMBA-TPA)

Published on: December 19, 2019

Related Concept Videos

The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
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...
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...
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 rapamycin-insensitive companion...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity: