Nav: Home

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

June 26, 2018

(PHILADELPHIA) -- 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, PhD, 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 prostate cancer that let them hone in on the process of resistance. The researchers found that as prostate cancer cells 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 prostate cancers 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 resistance. By hitting cancer cells 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 clinical trials with CDK 4/6 inhibitors in prostate cancer 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.
-end-
Related clinical trial: https://www.clinicaltrials.gov/ct2/show/NCT02555189

This study was funded by the NIH R01CA176401, R01CA217329, Prostate Cancer Foundation Young Investigator Awards, Prostate Cancer Foundation Challenge Award, Novartis, R01CA093237, National Institute of General Medical Sciences of the National Institutes of Health T32 GM008339, Department of Defense Prostate Cancer Research Program W81XWH-15-1-0236, New Jersey Health Foundation grant.

Article Reference: Renee de Leeuw, Christopher McNair, Matthew J. Schiewer, Neermala P Neupane, Lucas J Brand, Michael A. Augello, Zhen Li, Larry C Cheng, Akihiro Yoshida, Sean M Courtney, Starr Hazard, Gerald Hardiman, Maha Hussain, J. Alan Diehl, Justin M Drake, William K Kelly and Karen E. Knudsen, "MAPK reliance via acquired CDK4/6 inhibitor resistance in cancer," Clinical Cancer Research, DOI: 10.1158/1078-0432.CCR-18-0410, 2018.

Media Contact: Edyta Zielinska, edyta.zielinska@jefferson.edu, 215-955-7359.

Thomas Jefferson University

Related Prostate Cancer Articles:

The Lancet: Prostate cancer study finds molecular imaging could transform management of patients with aggressive cancer
Results from a randomised controlled trial involving 300 prostate cancer patients find that a molecular imaging technique is more accurate than conventional medical imaging and recommends the scans be introduced into routine clinical practice.
Common genetic defect in prostate cancer inspires path to new anti-cancer drugs
Researchers found that, in prostate cancer, a mutation leading to the loss of one allele of a tumor suppressor gene known as PPP2R2A is enough to worsen a tumor caused by other mutations.
First prostate cancer therapy to target genes delays cancer progression
For the first time, prostate cancer has been treated based on the genetic makeup of the cancer, resulting in delayed disease progression, delayed time to pain progression, and potentially extending lives in patients with advanced, metastatic prostate cancer, reports a large phase 3 trial.
Men taking medications for enlarged prostate face delays in prostate cancer diagnosis
University of California San Diego School of Medicine researchers report that men treated with medications for benign prostatic hyperplasia (enlarged prostate) experienced a two-year delay in diagnosis of their prostate cancer and were twice as likely to have advanced disease upon diagnosis.
CNIO researchers confirm links between aggressive prostate cancer and hereditary breast cancer
The study has potential implications for families with members suffering from these types of tumours who are at an increased risk of developing cancer.
Distinguishing fatal prostate cancer from 'manageable' cancer now possible
Scientists at the University of York have found a way of distinguishing between fatal prostate cancer and manageable cancer, which could reduce unnecessary surgeries and radiotherapy.
Researchers find prostate cancer drug byproduct can fuel cancer cells
A genetic anomaly in certain men with prostate cancer may impact their response to common drugs used to treat the disease, according to new research at Cleveland Clinic.
ASCO and Cancer Care Ontario update guideline on radiation therapy for prostate cancer
The American Society of Clinical Oncology (ASCO) and Cancer Care Ontario today issued a joint clinical practice guideline update on brachytherapy (internal radiation) for patients with prostate cancer.
Patient prostate tissue used to create unique model of prostate cancer biology
For the first time, researchers have been able to grow, in a lab, both normal and primary cancerous prostate cells from a patient, and then implant a million of the cancer cells into a mouse to track how the tumor progresses.
Moffitt Cancer Center awarded $3.2 million grant to study bone metastasis in prostate cancer
Moffitt researchers David Basanta, Ph.D., and Conor Lynch, Ph.D., have been awarded a U01 grant to investigate prostate cancer metastasis.
More Prostate Cancer News and Prostate Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Teaching For Better Humans 2.0
More than test scores or good grades–what do kids need for the future? This hour, TED speakers explore how to help children grow into better humans, both during and after this time of crisis. Guests include educators Richard Culatta and Liz Kleinrock, psychologist Thomas Curran, and writer Jacqueline Woodson.
Now Playing: Science for the People

#556 The Power of Friendship
It's 2020 and times are tough. Maybe some of us are learning about social distancing the hard way. Maybe we just are all a little anxious. No matter what, we could probably use a friend. But what is a friend, exactly? And why do we need them so much? This week host Bethany Brookshire speaks with Lydia Denworth, author of the new book "Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond". This episode is hosted by Bethany Brookshire, science writer from Science News.
Now Playing: Radiolab

Space
One of the most consistent questions we get at the show is from parents who want to know which episodes are kid-friendly and which aren't. So today, we're releasing a separate feed, Radiolab for Kids. To kick it off, we're rerunning an all-time favorite episode: Space. In the 60's, space exploration was an American obsession. This hour, we chart the path from romance to increasing cynicism. We begin with Ann Druyan, widow of Carl Sagan, with a story about the Voyager expedition, true love, and a golden record that travels through space. And astrophysicist Neil de Grasse Tyson explains the Coepernican Principle, and just how insignificant we are. Support Radiolab today at Radiolab.org/donate.