The findings were published in the Cancer Research journal, and ''reveal the combination of drugs to be dramatically more effective and less prone to resistance'' than a treatment-inhibiting KRAS approach alone.
While new drugs developed to inhibit KRAS — a gene that drives many types of cancer, especially pancreatic — are considered therapeutically promising, pancreatic cancer is especially drug-resistant, UC San Diego officials said. Most treatments are effective for a short time period, but the cancer finds its way around them.
Researchers said one potential reason is that a ''group of genes upstream of KRAS, called ERBB, appear to become upregulated in response to KRAS inhibition. In other words, when KRAS goes down, ERBB goes up and drives KRAS and other related genes back up again.''
KRAS inhibitors ''have the potential to completely change the landscape of treating pancreatic cancer,'' said Dr. Herve Tiriac, a co-senior author of the findings. ''However, we need to do a lot of upfront testing to optimize KRAS therapy, or clinical trials might get a lot of negative data,'' said Tiriac, an assistant research scientist at the UCSD School of Medicine and Moores Cancer Center.
Researchers confirmed that human pancreatic cells treated with the KRAS inhibitor MRTX1133, made by Mirati Therapeutics, become drug-resistant and increase ERBB.
However, pairing MRTX1133 with Afatinib — approved by the U.S. Food and Drug Administration — could combat that resistance, and also lower the number of surviving cancer cells.
Pancreatic cancer cells were ''exquisitely vulnerable'' to the two drugs, according to the study. The drug combo was tested on human pancreatic cancer cells, which are considered ''a step up'' from mouse models and the ''stage zero'' of human clinical trials.
Live mice treated with both drugs ''survived significantly longer than those treated with either drug alone,'' according to researchers.
UCSD study co-authors are Kevin Christian Montecillo Gulay, Xinlian Zhang, Jay Patel, Edgar Esparza, Deepa Sheik Pran Babu, Jonathan Weitz, Isabella Ng, Evangeline Mose and Minya Pu.Vasiliki Pantazopoulou, Satoshi Ogawa and Dannielle Engle, from the Salk Institute, also are co-authors.
Funding for the study was provided by the Lustgarten Foundation for Pancreatic Research, the Alexandrina M. McAfee Trust Foundation, the Research for a Cure of Pancreatic Cancer Fund and the Japan Society for the Promotion of Science.
