another door to shut to keep the "puppy" from escaping to the yard to chase squirrels
 

Sci Signal. 2015 May 26;8(378):ra52. doi: 10.1126/scisignal.aaa6922.
HER2-mTOR signaling-driven breast cancer cells require ER-associated degradation to survive
.
Singh N1, Joshi R1, Komurov K2.

Abstract
Targeting non-oncogenic vulnerabilities may provide additional therapeutic approaches in tumors that are resistant to oncogene-targeted therapy. Using a computational pathway-based approach, we interrogated clinical breast cancer genomic data sets for candidate non-oncogenic vulnerabilities in breast cancers that have genomic amplification of ERBB2, which encodes human epidermal growth factor 2 (HER2). HER2-positive (HER2(+)) breast cancers showed increased expression of genes encoding proteins in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Genetic ablation or pharmacological inhibition of ERAD led to irrecoverable ER stress and selectively killed HER2(+) breast cancer cells. Cell death caused by ERAD inhibition partially depended on increased HER2-mTOR signaling, which imposed an increased proteotoxic burden on the ER. Cell death in response to ER stress required the IRE1α-JNK pathway, which was selectively suppressed in HER2(+) breast cancers by phosphatases that inactivate JNK. Accordingly, the cytotoxicity of inhibiting ERAD as well as JNK phosphatases was synergistic in HER2(+) but not in HER2-negative breast cancer cells. Therefore, our study suggests that reactivation of oncogene-induced stress by targeting stress-adaptive pathways may be a beneficial approach for therapy-resistant breast cancers.
Copyright © 2015, American Association for the Advancement of Science.
PMID: 26012635 [PubMed - in process]

Re: another door to shut to keep the "puppy" from escaping to the yard to chase squir
 

As I soldier on from one drug combo to the next--and stay alive--I keep waiting and hoping for a new idea, a new pathway, a new "knockout punch" for the HER2. Where there's life there's hope, and I'm glad to be alive.

Thank you, Lani, for keeping us advised of new research.

Re: another door to shut to keep the "puppy" from escaping to the yard to chase squir
 

Layman's Terms please.......what is the door we need to shut to keep the puppies from chasing those squirrels. ;)

Re: another door to shut to keep the "puppy" from escaping to the yard to chase squir
 

linne, I truly thought those WERE layman's terms.

(((my "puppy" analogy posted previously:
Cancer is like a puppy dog that wants to get out of the house to chase the squirrels. Herceptin is like locking the front door. They puppy may learn it is possible to get out to play with the squirrels by going out the backdoor instead (eg, using her3, EGFR, IGFR, ER, etc paths to escape the blockade of the her2 pathway). Giving chemo is often like accelerating the aging of the puppy. It gets taller and able to jump on the dresser and jump out the window!!

For Stage IVs, it is usually just a question of what they will add next to herceptin if monotherapy is inssufficient to keep it from progressing(like which window/door to close in addition in the case of the puppy) )))

The long words in the abstract describing the ERAD PATHWAY merely describe another window
that needs to be closed to prevent the puppy from escaping to the backyard to wreak havoc chasing the squirrels ie, preventatively blockingia another possible escape route cancer tries to take.Cancer consistently tries to adapt (evolution in real-time) to escape considering previously blocked routes of escape as its goal of relentless growth and migration is not easily thwarted.

GOOD ENOUGH?

Re: another door to shut to keep the "puppy" from escaping to the yard to chase squir
 

Lani--

I love your puppy and squirrels analogies. And, again, thanks for posting results of emergent research and wisdom.

Love,
Amy

Re: another door to shut to keep the "puppy" from escaping to the yard to chase squir
 

Lani! Brilliant analogy! Works for me! Thank yu so much for your tireless work. Thank you very much!