Limits...
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 induces miR-21 to inhibit negative regulators of downstream EGFR pathways. Induction of miR-21 occurs upon AP-1 activation in response to EGFR/RalGDS/ JNK signaling. MiR-21 targets the PDCD4 and PTEN tumor suppressors to achieve maximal Ras/RalGDS/JNK/AP-1 and Ras/PI3K/Akt signaling. MiR-21 targets the ligand-induced negative RTK feed-back regulator, SPRY, to maintain prolonged Ras/Raf/Erk signaling.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3860350&req=5

f2: EGFR induces miR-21 to inhibit negative regulators of downstream EGFR pathways. Induction of miR-21 occurs upon AP-1 activation in response to EGFR/RalGDS/ JNK signaling. MiR-21 targets the PDCD4 and PTEN tumor suppressors to achieve maximal Ras/RalGDS/JNK/AP-1 and Ras/PI3K/Akt signaling. MiR-21 targets the ligand-induced negative RTK feed-back regulator, SPRY, to maintain prolonged Ras/Raf/Erk signaling.

Mentions: In GBM, inhibition of miR-21 activity increased PTEN expression and decreased tumorigenicity, EGFR expression and Akt activation102. MiR-21 is positively regulated by EGFR in cancer cells as demonstrated by the finding that AG1478, an EGFR-TKI, blocked EGFR induction of miR-2198. Interestingly, activation of the EGFR family member, ErbB2, induced miR-21 to promote cell invasion through suppression of the well-established miR-21 target, PDCD499. Critically, oncogenic HRasG12V was sufficient to induce miR-2199, consistent with oncogenic Ras mutants conferring resistance to EGFR-TKIs65. The discovery of a novel autoregulatory loop revealed that miR-21 targets PDCD4, a negative AP-1 regulator, upon its induction by AP-1 in response to Ras signaling101, and several other studies confirmed that miR-21 is positively regulated by Ras/ERK signaling103,118,119. Interestingly, data from transgenic tumor models show that miR-21 drives tumorigenesis by repressing negative regulators of the Ras/MEK/ERK, Ras/PI3K/Akt and Ras/RalGDS/JNK pathways, thus further demonstrating that miR-21 acts as an effector of Ras to promote transformation103,104. Collectively, these reports suggest that EGFR family members positively regulate miR-21 as a means to achieve a signaling threshold required for transformation and the maintenance of malignant cellular phenotypes (Figure 2).


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 induces miR-21 to inhibit negative regulators of downstream EGFR pathways. Induction of miR-21 occurs upon AP-1 activation in response to EGFR/RalGDS/ JNK signaling. MiR-21 targets the PDCD4 and PTEN tumor suppressors to achieve maximal Ras/RalGDS/JNK/AP-1 and Ras/PI3K/Akt signaling. MiR-21 targets the ligand-induced negative RTK feed-back regulator, SPRY, to maintain prolonged Ras/Raf/Erk signaling.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: EGFR induces miR-21 to inhibit negative regulators of downstream EGFR pathways. Induction of miR-21 occurs upon AP-1 activation in response to EGFR/RalGDS/ JNK signaling. MiR-21 targets the PDCD4 and PTEN tumor suppressors to achieve maximal Ras/RalGDS/JNK/AP-1 and Ras/PI3K/Akt signaling. MiR-21 targets the ligand-induced negative RTK feed-back regulator, SPRY, to maintain prolonged Ras/Raf/Erk signaling.
Mentions: In GBM, inhibition of miR-21 activity increased PTEN expression and decreased tumorigenicity, EGFR expression and Akt activation102. MiR-21 is positively regulated by EGFR in cancer cells as demonstrated by the finding that AG1478, an EGFR-TKI, blocked EGFR induction of miR-2198. Interestingly, activation of the EGFR family member, ErbB2, induced miR-21 to promote cell invasion through suppression of the well-established miR-21 target, PDCD499. Critically, oncogenic HRasG12V was sufficient to induce miR-2199, consistent with oncogenic Ras mutants conferring resistance to EGFR-TKIs65. The discovery of a novel autoregulatory loop revealed that miR-21 targets PDCD4, a negative AP-1 regulator, upon its induction by AP-1 in response to Ras signaling101, and several other studies confirmed that miR-21 is positively regulated by Ras/ERK signaling103,118,119. Interestingly, data from transgenic tumor models show that miR-21 drives tumorigenesis by repressing negative regulators of the Ras/MEK/ERK, Ras/PI3K/Akt and Ras/RalGDS/JNK pathways, thus further demonstrating that miR-21 acts as an effector of Ras to promote transformation103,104. Collectively, these reports suggest that EGFR family members positively regulate miR-21 as a means to achieve a signaling threshold required for transformation and the maintenance of malignant cellular phenotypes (Figure 2).

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