Novel therapy-resistance mechanism promoting the growth of breast cancer brain metastasis

January 29, 2021

SORLA is a protein trafficking receptor that has been mainly studied in neurons, but it also plays a role in cancer cells. Professor Johanna Ivaska's research group at Turku Bioscience observed that SORLA functionally contributes to the most reported therapy-resistant mechanism by which the cell-surface receptor HER3 counteracts HER2 targeting therapy in HER2-positive cancers. Removing SORLA from cancer cells sensitized anti-HER2 resistant breast cancer brain metastasis to targeted therapy.

HER2 protein is a strong driver of tumor growth. HER2 amplification occurs in about 20 % of breast cancers and overexpression or amplification of HER2 is also commonly found in bladder and gastric cancers. HER2 targeting therapies, such as Herceptin, are widely used in clinical care and it plays an important role in the treatment of HER2-positive cancers.

However, some patients will eventually progress during the Herceptin treatment and therapy resistance is frequently linked to the upregulation of HER3 receptor. The newly discovered role of SORLA in supporting HER3 expression and drug resistance offers novel possibilities to target drug-resistant HER2 positive cancers in the future.

"HER2 tumors can become therapy resistant by upregulating HER3. Currently these tumors are un-druggable as there are no HER3 targeted therapies available. Our study showed that removing SORLA protein from drug-resistant HER2-positive cancer cell lines sensitized breast cancer brain metastasis to anti-HER2 therapy. To date, very little has been known about SORLA in cancer. Our discovery that HER3 receptor-induced drug resistance is dependent on SORLA was surprising, since this cancer type and its resistance mechanisms have already been widely studied," says lead author, Post-doctoral Researcher Hussein Al-Akhrass from Turku Bioscience at the University of Turku, Finland.

New understanding of these mechanisms enabled the possibility to control the growth of breast cancer cells in their most aggressive situation when they form tumors in the brain.

In vitro cell culture experiments showed that SORLA protein promotes the recycling of HER3 receptor back to plasma membrane, where the receptor is active and drives the proliferation of cancer cells. When SORLA was removed, HER3 receptor was destroyed in cells leading to sensitization of the cells to anti-HER2 therapy.

The next goal for the research group is to find a way to block the function of SORLA in tumor cells and therefore if there could be a way to develop SORLA targeting treatment.
-end-
The Ivaska lab is located in Turku Bioscience that is operated by the University of Turku and Åbo Academy University in Finland. The study was funded by Finnish Cancer Organisations and Sigrid Juselius Foundation.

University of Turku

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.