A UNC Lineberger Comprehensive Cancer Center patient’s selfless act has generated insights into a cancer gene mutation that has proven to be so pervasive and perplexing that it has confounded researchers for decades. It even spurred the National Cancer Institute to develop an entire initiative to try to solve numerous mysteries involving RAS gene mutations.
In findings reported January 2022 in the Journal of Clinical Investigation, UNC Lineberger’s Chad Pecot, MD, and colleagues revealed how they used tissue and tumor specimens from the patient just after he succumbed to lung cancer to unravel how a KRAS mutation (the most common mutation in the RAS family) developed resistance to a new treatment that had initially proved effective.
“To my knowledge, this is the first and only study in the world thus far using autopsy samples to explore how tumors become resistant to drugs that inhibit KRAS. Ours was a unique approach and we learned a lot from it,” said Pecot, an associate professor of medicine. “It is extremely powerful when a patient decides to contribute to scientific and medical knowledge by making a very deliberate sacrifice. His decision will have a ripple effect that will be eternal.”
The patient, Richard Duley, had a special and close association with UNC Lineberger – and Pecot’s clinic and laboratory in particular.
Lung cancer research and a patient’s wish
Duley was 76 when he was diagnosed with a type of KRAS-mutated non-small cell lung cancer called G12C. He received chemotherapy and immunotherapy, but although his disease initially responded, the tumors eventually began to grow. He then received a new drug, sotorasib, that the U.S. Food and Drug Administration approved in May 2021 for his very specific type of lung cancer. The drug is the first of its kind and it directly inhibits the mutated KRAS protein, which results in an “off switch” within the tumor.
Duley was quite ill when he started receiving sotorasib as part of an early-phase clinical trial. He could barely talk or swallow because tumors were growing in his neck. Within three days after starting the sotorasib tablets, Duley reported that he felt “fantastic,” and even went shopping and ran errands. He continued to receive the drug for 17 weeks.
Back in the clinic, the first of several imaging scans showed that, on average, most of his tumors had shrunk by about a third. Duley reported that he continued to feel quite well. This allowed him to reunite with family members, have a good quality of life, and feel normal again.
Unfortunately, after about four months the drug quit working, and subsequent imaging scans showed the lung cancer had come roaring back.
“Mr. Duley believed in me as a doctor but also as a scientist. He donated funds to my research endeavors and that had tremendous value to me. I spent a little bit of it on high-risk ideas, and he loved hearing about things we discovered,” Pecot said. “Near the end of his life he told me he wanted to donate his body to scientific research ‘so the world could learn something in my death.’”
Rapid approach yields findings for researchers
In line with Duley’s request, about two dozen tissue samples were collected within hours of his death. The ability to rapidly acquire the samples made them particularly valuable for research purposes. Pecot and his team used RNA and DNA sequencing to study thousands of genes from both pre- and post-treatment biospecimens to try to determine why his tumors were able to eventually become resistant to sotorasib.
The researchers found many mechanisms that were employed by cancer cells in the tumors that ultimately returned. Some were expected, such as those that reactivated tumor signaling pathways. In particular, transforming growth factor-beta (TGF-β), a prevalent and multifunctional protein that is critical in cell signaling, was among the most important factors in reactivating numerous cancer pathways, according to the researchers. The investigators also found that cancer cells were able to re-establish blood flow to the tumors to help feed the tumors’ growth. They also found the resistant tumors were able to “hide” from the immune system, and the tumors had very reduced levels of immune cells.
The gift of supporting research
Fran Duley, Richard’s wife, said her late husband reacted to life and death with gusto and he would be pleased to know he was able to contribute to Pecot’s research. “He did not like warm and fuzzy! His reaction to this amazing study and the results would be ‘Do More. Don’t stop.’ I am so grateful to everyone at every level of Richard’s care and the post-research, especially Dr. Pecot. I cannot totally explain the morphing of doctor, to healer, to friend. But [Dr. Pecot] was so special to Rich and is so reassuring to me.”
“We learned so much from one patient. But there is much work to do from here, including testing drug combinations, as we looked at just one drug in this study,” Pecot said. “I do want to highlight something special about this research effort – it was due to a courageous and selfless gift, and I feel honored to have been a part of it.”
Study authors and disclosures
In addition to Pecot, the other authors of the Journal of Clinical Investigation study are Yihsuan S. Tsai, PhD, Mark G. Woodcock, MD, Salma H. Azam, PhD, Leigh B. Thorne, MD, Krishna L. Kanchi, DVM, MS, Joel S. Parker, PhD, and Benjamin G. Vincent, MD, all from UNC.
This research was supported by donations from Richard and Fran Duley and Jimmy and Kay Mann. Grant support also came from National Institutes of Health awards R01CA215075, R01CA258451, R41CA246848, 1T32CA211056 and an NCBC TRG award.
Pecot and Azam, hold intellectual property interests and issued U.S. patents related to KRAS targeting technologies. Pecot is the founder of EnFuego Therapeutics, Inc. and holds equity in the company. No other authors have a declared conflict of interest.