Researchers have found a link between genetic mutations and resistance to cancer treatment

researchers from Rogel Cancer Center at the University of MichiganBy studying the molecular landscape of more than 500 patients with an aggressive form of multiple myeloma, he discovered the prevalence of active major cancer pathways in these patients, far more than previously thought. over 45-65% of the NF-κB and RAS/MAPK pathways each have modifications. The study was published in Nature Communications.

additional, Arul Shinayan, MD, PhD.D., director of the Michigan Center for Translational Pathology, and his team have found a link between mutations and RASopathies, a particular group of genetic syndromes, in patients with relapsed treatment-resistant multiple myeloma. This was the first observation of its kind.

The team compared the molecular makeup of patients with untreated multiple myeloma with those with a treatment-resistant version of the disease. Comparing these patients allowed the researchers to describe the drivers of the more aggressive form of multiple myeloma.

“It also led us to discover the mechanisms of resistance that occur in patients who relapse and are resistant to treatment,” said Chenyan. “We found that more than a quarter of patients have developed some kind of resistance mechanism. The genetic modifications that occur in these patients make them resistant to commonly used treatments for multiple myeloma.”

This study was funded by Multiple Myeloma Research Foundation It included patient samples from the Multiple Myeloma Research Consortium – a collaborative network of 22 leading cancer centers focused on investigating the most promising early-stage treatments. Clinical sequencing powered by Mi-Oncoseq In Michigan Medicine, directed by Chinnaiyan and Dan Robinson, Ph.D.. From the knowledge gained through this work, the researchers initiated a study that assigns patients individual arms to a clinical trial based on their molecular profile to match alterations with potential treatments using a comprehensive sequence-based approach.

Chenian says that while this current study was a retrospective, he’s optimistic about the future. “We are developing the tools and knowledge to translate these strategies into actual clinical impact on patients.”

“Treatment of relapsed multiple myeloma can be very challenging despite the tremendous progress we have made,” said Hearn Jay Cho, PhD, chief medical officer of MMRF. Uncovering new targets and therapies according to which they act may be useful in the future for patients who develop resistance to current treatments such as monoclonal antibodies that target CD38. In keeping with our mission, MMRF is committed to supporting research initiatives that accelerate the discovery of new treatments and more advanced care for all patients with multiple myeloma. “

Paper cited: “Genetic heterogeneity and drug resistance mechanisms of relapsed-resistant multiple myeloma,” Nature Communications. DOI: 10.1038 / s41467-022-31430-0

Additional authors: Josh En Fu, Yi Mi Wu, Jenmarie Michler, Sarah Hall, Rahul Manan, Lisha Wang, Yu Ning, Jin Zhou, Alexander C. Hopkins, James C. Estill, Wallace KP Chan, Jennifer Yesil, Zhuhong Kao, Arvind Rao, Alexander Tsudikov , Moshe Talbaz, Craig E. Cole, Jing Si Ye, Multiple Myeloma Research Consortium, B. Liv Bergsagel, Daniel Auclair, Hearn Jay Chou, Dan R. Robinson

Funding: Multiple Myeloma Research Foundation (ORSP 19-PAF05802); National Cancer Institute (NCI, grant R35-CA231996); Early Detection Research Network (grant U01-CA214170); Prostate Cancer Foundation. JNV and AMC are supported by funding from the NCI Clinical Tumor Analysis Proteomic Consortium (grant U24-CA210967). AMC is an investigator with the Howard Hughes Medical Institute, an Alfred Tubman researcher, and a professor at the American Cancer Society.

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