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The evolution of advanced cancer care has experienced the growth of precision medicine, in which targeted drugs can offer more individualized options for each patient based on their tumor-specific biology. However, cancer cells often find ways to develop resistance to many targeted therapies, allowing tumors to continue growing or recur after treatment.

A team of scientists at VCU Massey Comprehensive Cancer Center has discovered a new combination therapy —sotorasib and an experimental drug called FGTI-2734—that overcomes drug resistance and makes targeted treatment more effective in lung tumors harboring a specific mutation. Their findings were featured on the cover of the latest volume of the Journal of Thoracic Oncology.

“This could be a paradigm shift in how we treat lung cancer,” said study lead Said Sebti, Ph.D., Massey’s associate director for basic research and Lacy Family Chair in Cancer Research. “We’re hoping to give patients a fighting chance against resistance.”

Lung cancer is the leading cause of cancer death in the U.S. Mutations in the KRAS gene are responsible for approximately one-third of all cancers, as indicated by the National Cancer Institute. A subset of those mutations called KRAS G12C is present in about 14% of all non-small cell lung cancers, making it the predominant form of the KRAS mutation in all lung tumors. KRAS G12C is the only mutation within the KRAS family for which there is FDA-approved targeted drugs. These drugs are known as sotorasib and adagrasib, and they essentially block the function of the KRAS G12C gene that leads to uncontrolled cell growth.

While sotorasib and adagrasib have transformed the landscape of lung cancer treatment by extending progression-free survival for some patients, the majority of tumors fight back against these drugs, where patients never respond to these therapies in the first place or they build up a resistance over time and their disease relapses.

For example, in a sample size of 100 patients with the KRAS G12C mutation, only about 35 of them will respond to the drugs, leaving about 65 patients for whom the drugs are not effective at all. Of the 35 patients who do respond initially, on average, their tumors will relapse in about six to seven months.

"This is precision medicine, and you would expect every lung cancer patient with the KRAS G12C mutation to respond to sotorasib treatment, but they don’t,” said Sebti, who is also a professor in the Department of Pharmacology and Toxicology at the VCU School of Medicine. “If you can understand why this is happening, then you can design strategies to overcome sotorasib resistance."

To try to answer this question, while reviewing the previous literature, Sebti realized that although tumors from lung cancer patients treated with sotorasib alone develop different ways of drug resistance, they all shared a common theme.

“When we looked at all those different ways that each tumor was trying to fight back against sotorasib, we noticed that the majority of them were related to this cellular process called ERK reactivation,” Sebti said.

ERK belongs to a family of protein kinases — enzymes that selectively modify the function of other proteins — that regulates communication within cells and is heavily involved in resistance to multiple targeted cancer treatments, including sotorasib. In order to mount an effective defense against sotorasib, ERK requires wild type RAS — non-mutated forms of the RAS gene —cellular membrane localization within cancer cells.

Sebti and his collaborators discovered that if you can block wild type RAS from localizing to cellular membranes within the tumors, you may be able to prevent ERK from fighting back against the initial treatment. This might pave the way to overcome resistance and effectively kill the lung tumors with the KRAS G12C mutation.

Using a drug known as FGTI-2734 — a drug co-invented by Sebti while he was at the Moffitt Cancer Center and Andrew Hamilton, Ph.D., while he was at Yale University — in combination with sotorasib, the Massey researchers were able to completely shut down the means by which these tumors were able to build up a resistance to the treatment.

“The rational combination of FGTI-2734 with sotorasib causes lung cancer cells to panic and die, introducing an entirely novel strategy for treating lung tumors with this specific mutation,” Sebti said.

These findings were demonstrated in patient-derived cancer cells evaluated in the lab setting both in vitro and in animal models, but the combination treatment strategy has yet to be tested in patients in the clinic. The Massey team is working toward securing FDA approval for clinical trials — a crucial step toward bringing this innovation to patients. Although the path from the laboratory to an FDA-approved therapy is long, Sebti said these preclinical findings are significant and encouraging.

“Every researcher’s dream in this noble field of research is to have a real impact on cancer patients,” added Sebti. “This discovery may realize this dream by eventually leading to better outcomes and longer lives for people facing lung cancer.”

The editor-in-chief of the Journal of Thoracic Oncology authored a breakdown of this research in the March issue of the journal, and a group of international scientists wrote an accompanying editorial detailing their perspective on these findings.

Sebti’s collaborators on this study include his Massey lab members Aslamuzzaman Kazi, Ph.D., Deblina Ghosh, Ph.D., Hitesh Vasiyani, Ph.D., of the Department of Pharmacology and Toxicology at the VCU School of Medicine; Jose Trevino, M.D.; and Rachit Shah, M.D., and Vignesh Vudatha, M.D., of the Department of Surgery at the VCU School of Medicine; and Dipankar Bandyopadhyay, Ph.D., from the Department of Biostatistics at the VCU School of Medicine.

This research was funded by the National Cancer Institute (R35 CA197731-01, P30 CA016059).

Written by: Blake Belden