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Therapeutic resistance in cancer: microRNA regulation of EGFR signaling networks.

Gomez GG, Wykosky J, Zanca C, Furnari FB, Cavenee WK - Cancer Biol Med (2013)

Bottom Line: However, limited therapeutic benefits to cancer patients have been derived from EGFR-targeted therapies.Here, we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs (miRs) as downstream effector molecules utilized by EGFR to promote tumor initiation, progression and that play a role in resistance to EGFR inhibitors.We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.

ABSTRACT
Receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor (EGFR) regulate cellular homeostatic processes. EGFR activates downstream signaling cascades that promote tumor cell survival, proliferation and migration. Dysregulation of EGFR signaling as a consequence of overexpression, amplification and mutation of the EGFR gene occurs frequently in several types of cancers and many become dependent on EGFR signaling to maintain their malignant phenotypes. Consequently, concerted efforts have been mounted to develop therapeutic agents and strategies to effectively inhibit EGFR. However, limited therapeutic benefits to cancer patients have been derived from EGFR-targeted therapies. A well-documented obstacle to improved patient survival is the presence of EGFR-inhibitor resistant tumor cell variants within heterogeneous tumor cell masses. Here, we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs (miRs) as downstream effector molecules utilized by EGFR to promote tumor initiation, progression and that play a role in resistance to EGFR inhibitors. We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms.

No MeSH data available.


Related in: MedlinePlus

EGFR mutations in GBM and NSCLC. Tumor-type specific mutations of EGFR are well-established. In GBM, EGFR undergoes deletion processes that lead to the expression of truncated mutants, of which EGFRvIII is the major form that is associated with a poor response to conventional and EGFR-TKIs therapies. Point mutations of the EGFR kinase domain are predominant in NSCLC.
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f1: EGFR mutations in GBM and NSCLC. Tumor-type specific mutations of EGFR are well-established. In GBM, EGFR undergoes deletion processes that lead to the expression of truncated mutants, of which EGFRvIII is the major form that is associated with a poor response to conventional and EGFR-TKIs therapies. Point mutations of the EGFR kinase domain are predominant in NSCLC.

Mentions: Various EGFR mutations are well-documented and shown to be tumor-type specific. One mutation with profound pathologic effects is a truncated form of EGFR, commonly found in about 50% of GBMs with EGFR amplification9, named EGFRvIII (also known as ΔEGFR, EGFR* or de2-7EGFR)20. EGFRvIII lacks a portion of the extracellular ligand-binding domain, is constitutively active and slowly recycled. EGFRvIII does not bind ligand but initiates constitutive mitogenic and cell survival signals21, and a resulting worse prognosis for GBM patient whose tumors express it22. Other truncation mutants of EGFR (EGFRvII; EGFRvV) have less demonstrated clinical relevance23 (Figure 1).


Therapeutic resistance in cancer: microRNA regulation of EGFR signaling networks.

Gomez GG, Wykosky J, Zanca C, Furnari FB, Cavenee WK - Cancer Biol Med (2013)

EGFR mutations in GBM and NSCLC. Tumor-type specific mutations of EGFR are well-established. In GBM, EGFR undergoes deletion processes that lead to the expression of truncated mutants, of which EGFRvIII is the major form that is associated with a poor response to conventional and EGFR-TKIs therapies. Point mutations of the EGFR kinase domain are predominant in NSCLC.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3860350&req=5

f1: EGFR mutations in GBM and NSCLC. Tumor-type specific mutations of EGFR are well-established. In GBM, EGFR undergoes deletion processes that lead to the expression of truncated mutants, of which EGFRvIII is the major form that is associated with a poor response to conventional and EGFR-TKIs therapies. Point mutations of the EGFR kinase domain are predominant in NSCLC.
Mentions: Various EGFR mutations are well-documented and shown to be tumor-type specific. One mutation with profound pathologic effects is a truncated form of EGFR, commonly found in about 50% of GBMs with EGFR amplification9, named EGFRvIII (also known as ΔEGFR, EGFR* or de2-7EGFR)20. EGFRvIII lacks a portion of the extracellular ligand-binding domain, is constitutively active and slowly recycled. EGFRvIII does not bind ligand but initiates constitutive mitogenic and cell survival signals21, and a resulting worse prognosis for GBM patient whose tumors express it22. Other truncation mutants of EGFR (EGFRvII; EGFRvV) have less demonstrated clinical relevance23 (Figure 1).

Bottom Line: However, limited therapeutic benefits to cancer patients have been derived from EGFR-targeted therapies.Here, we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs (miRs) as downstream effector molecules utilized by EGFR to promote tumor initiation, progression and that play a role in resistance to EGFR inhibitors.We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.

ABSTRACT
Receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor (EGFR) regulate cellular homeostatic processes. EGFR activates downstream signaling cascades that promote tumor cell survival, proliferation and migration. Dysregulation of EGFR signaling as a consequence of overexpression, amplification and mutation of the EGFR gene occurs frequently in several types of cancers and many become dependent on EGFR signaling to maintain their malignant phenotypes. Consequently, concerted efforts have been mounted to develop therapeutic agents and strategies to effectively inhibit EGFR. However, limited therapeutic benefits to cancer patients have been derived from EGFR-targeted therapies. A well-documented obstacle to improved patient survival is the presence of EGFR-inhibitor resistant tumor cell variants within heterogeneous tumor cell masses. Here, we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs (miRs) as downstream effector molecules utilized by EGFR to promote tumor initiation, progression and that play a role in resistance to EGFR inhibitors. We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms.

No MeSH data available.


Related in: MedlinePlus