When one drug fails, a new door opens for cancer treatment

June 26, 2018, Thomas Jefferson University

A new class of cancer drugs—called CDK4/6 inhibitors—recently approved to treat breast cancer can stunt the cancer's growth and replication. It is also being explored for a number of other cancers. Unfortunately, patients often develop resistance to the therapy, and the cause of that resistance has been difficult to pin down. Researchers at the Sidney Kimmel Cancer Center at Jefferson Health recently discovered the key resistance mechanism in prostate cancer and identified a molecular inhibitor that could help fight the disease when resistance develops.

"We provide evidence that a drug, already in development, could help fight the cancers that develop resistance to CDK4/6 inhibitors," said senior author Karen E. Knudsen, Ph.D., Director of the Sidney Kimmel Cancer Center at Jefferson Health. "This could potentially offer patients a more effective therapy to try when the CDK4/6 inhibitors fail."

The results were recently published in the journal Clinical Cancer Research.

In order to first explore how tumors become resistant to CDK4/6-inhibitor therapy, Dr. Knudsen and her team, including first author Renée de Leeuw, used a cellular model of cancer that let them hone in on the process of resistance. The researchers found that as become resistant to CKD4/6-inhibitors they rewire the protein pathways essential for their survival. The transcriptome of the cancer cells fundamentally shifts. This rewiring causes the cells to begin to depend on a different pathway for their growth, the MAPK-6 or MEK pathway, which normally does not play a big role in prostate cancer.

The researchers also showed, when the develop resistance to the CDK4/6 inhibitors and switch to being dependent on the MAPK-6 pathway, the cancer cells become much more aggressive, spreading and seeding metastases more rapidly in mouse models of the disease.

"However, this new dependence offers us an opportunity," said Dr. Knudsen. "MEK-inhibitors are currently being tested and in clinical trials. While these drugs show limited impact on earlier stages of disease they may become effective therapies as prostate cancer cells—and potentially other cancers as well—develop CDK4/6 . By hitting cancer with one therapy, namely the CDK4/6 inhibitors, followed by a MEK inhibitor, we block the cancer's avenues of escaping death one by one."

MEK inhibitors have been approved for treating melanoma and are currently being tested for prostate cancer in clinical trials. But there are no currently open trials investigating the combination treatment with a MEK and CDK4 inhibitors together. "These studies will be instrumental in guiding the next generation of with CDK 4/6 inhibitors in prostate and gives us a strong rationale to target MEK pathway," said co-author W. Kevin Kelly, DO, Professor of Medical Oncology, Director of the Division of Solid Tumor Oncology, and leader of the Prostate Cancer Program at the Sidney Kimmel Cancer Center, which is recognized by the National Cancer Institute as one of eight Prostate Cancer Centers of Excellence.

Explore further: New targeted therapy schedule could keep melanoma at bay

More information: Renee de Leeuw et al, MAPK reliance via acquired CDK4/6 inhibitor resistance in cancer, Clinical Cancer Research (2018). DOI: 10.1158/1078-0432.CCR-18-0410

Related clinical trial: www.clinicaltrials.gov/ct2/show/NCT02555189

Related Stories

New targeted therapy schedule could keep melanoma at bay

March 26, 2018
Skin melanoma, a particularly insidious cancer, accounts for the vast majority skin cancer deaths and is one of the most common cancers in people under 30. Treatment for advanced melanoma has seen success with targeted therapies ...

Breast cancer resistance to CDK4/6 inhibitors arises in many ways

March 28, 2016
Breast cancer cells became resistant to therapeutics targeting CDK4/6, such as palbociclib (Ibrance), in multiple ways, and preclinical studies suggested different combinations of therapeutics may prevent and overcome the ...

Discovery of new prostate cancer biomarkers could improve precision therapy

August 14, 2017
Mayo Clinic researchers have identified a new cause of treatment resistance in prostate cancer. Their discovery also suggests ways to improve prostate cancer therapy. The findings appear in Nature Medicine. In the publication, ...

RB1 gene mutations underlie clinical resistance to CDK 4/6 inhibitor breast cancer therapy

April 11, 2018
A multi-institutional research team has identified what may be a novel mechanism underlying acquired resistance to CDK 4/6 inhibitor treatment for breast cancer. In their report published in the Annals of Oncology, the team—led ...

Study shows how certain drugs alter metabolism of pancreatic cancer cells

January 21, 2016
UT Southwestern Medical Center researchers have found that cancer drugs known as CDK4/6-inhibitors alter the metabolism of pancreatic cancer cells, revealing a biologic vulnerability that could be exploited for therapeutic ...

Study uncovers an additional strategy for targeting treatment-resistant prostate cancer

May 2, 2017
Prostate cancer cells depend on signaling through the androgen receptor (AR) to grow and survive. Many anti-cancer therapies that target ARs are initially successful in patients, including a class of drugs known as CYP17A1 ...

Recommended for you

Scientists discover new method of diagnosing cancer with malaria protein

August 17, 2018
In a spectacular new study, researchers from the University of Copenhagen have discovered a method of diagnosing a broad range of cancers at their early stages by utilising a particular malaria protein that sticks to cancer ...

Pregnant? Eating broccoli sprouts may reduce child's chances of breast cancer later in life

August 16, 2018
Researchers at the University of Alabama at Birmingham have found that a plant-based diet is more effective in preventing breast cancer later in life for the child if the mother consumed broccoli while pregnant. The 2018 ...

Three scientists share $500,000 prize for work on cancer therapy

August 15, 2018
Tumors once considered untreatable have disappeared and people previously given months to live are surviving for decades thanks to new therapies emerging from the work of three scientists chosen to receive a $500,000 medical ...

PARP inhibitor improves progression-free survival in patients with advanced breast cancers

August 15, 2018
In a randomized, Phase III trial led by researchers at The University of Texas MD Anderson Cancer Center, the PARP inhibitor talazoparib extended progression-free survival (PFS) and improved quality-of-life measures over ...

New clues into how 'trash bag of the cell' traps and seals off waste

August 15, 2018
The mechanics behind how an important process within the cell traps material before recycling it has puzzled scientists for years. But Penn State researchers have gained new insight into how this process seals off waste, ...

RUNX proteins act as regulators in DNA repair, study finds

August 15, 2018
A study by researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore has revealed that RUNX proteins are integral to efficient DNA repair via the Fanconi Anemia (FA) ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.