Targeting integrin-linked kinase to suppress oncogenic KRAS signaling in pancreatic cancer

Po Chen Chu, Samuel K. Kulp, Tanios Bekaii-Saab, Ching Shih Chen

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Although oncogenic KRAS represents a therapeutically relevant target in pancreatic cancer, it is deemed “non-druggable” because of the intrinsic difficulty in designing direct inhibitors of KRAS. Our recent work demonstrated a KRAS-integrin-linked kinase (ILK) regulatory feedback loop that allows pancreatic cancer cells to regulate KRAS expression and to interact with the tumor microenvironment to promote aggressive phenotype. KRAS induces E2F1-mediated transcriptional activation of ILK expression, and ILK, in turn, controls KRAS expression via hnRNPA1, which binds and destabilizes the G-quadruplex in the KRAS promoter. Moreover, ILK inhibition blocked KRAS-driven EMT and growth factor-stimulated KRAS expression. This regulatory loop, however, was not noted in KRAS mutant colorectal and lung cancer cells examined as knockdown of KRAS or ILK did not affect each other's expression, suggesting that this KRAS-ILK feedback regulation is specific for pancreatic cancer. In sum, this regulatory loop provides a strong mechanistic rationale for suppressing oncogenic KRAS signaling through targeting ILK, and this creating a potential new therapeutic strategy for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1-5
Number of pages5
JournalSmall GTPases
DOIs
StateAccepted/In press - Dec 8 2016

Fingerprint

Pancreatic Neoplasms
Cells
G-Quadruplexes
Feedback
Tumor Microenvironment
integrin-linked kinase
Transcriptional Activation
Tumors
Colorectal Neoplasms
Lung Neoplasms
Intercellular Signaling Peptides and Proteins
Chemical activation
Phenotype

Keywords

  • autoregulatory loop
  • heterogeneous nuclear ribonucleoprotein A1
  • integrin-linked kinase
  • Oncogenic KRAS
  • pancreatic cancer

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Targeting integrin-linked kinase to suppress oncogenic KRAS signaling in pancreatic cancer. / Chu, Po Chen; Kulp, Samuel K.; Bekaii-Saab, Tanios; Chen, Ching Shih.

In: Small GTPases, 08.12.2016, p. 1-5.

Research output: Contribution to journalArticle

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