[Mar. 9, 2023: Meagan Raeke, UPenn School of Medicine]
A small molecule inhibitor that tackles the hard-to-target genetic mutation that causes cancer kras, found in nearly 30% of all human tumors. (CREDIT: Creative Commons)
A small molecule inhibitor that tackles the hard-to-target genetic mutation that causes cancer kras, found in nearly 30% of all human tumors, was successful in shrinking tumors or stopping cancer growth in preclinical models of pancreatic cancer, researchers at Penn Medicine’s Abramson Cancer Center have shown, suggesting that the drug is a strong candidate for clinical trials. The study was published in Discovery of cancera journal of the American Association for Cancer Research.
“The results of this study are in stark contrast to anything we’ve seen before in pancreatic cancer,” said co-corresponding lead author Ben Stanger, MD, PhD, Hanna Wise Professor of Cancer Research at the Perelman School of Medicine at the University of Pennsylvania and director of the Penn Pancreatic Cancer Research Center. “Even in preclinical research models for this type of cancer, most drugs tested over the past decade – including new immunotherapies – have had limited impact.”
Patients with pancreatic cancer have a poor overall prognosis with an 11% five-year survival rate and limited treatment options. Nearly 90% of pancreatic cancers are due to a mutation in kras gene, the most common oncogene in all types of cancer. The first targeted therapy for kras was approved last year for non-small cell lung cancer with KRAS G12C mutations, but only 2% of pancreatic cancers express this type of mutation. About 36 percent of pancreatic cancers with a kras mutations are KRAS G12D-mutant.
The small molecule inhibitor used in this study, MRTX1133 (developed by Mirati Therapeutics) specifically targets KRAS G12D, as the company first reported last month in natural medicine.
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Penn’s study now shows kras-the inhibitor not only targets cancer cells directly, but also unexpectedly cooperates with the immune system to produce a lasting response to treatment, which is important because cancer eventually finds a way to escape most therapies targeted.
“We have known since KRAS G12C studies and other targeted therapeutic studies that resistance is going to occur,” Stanger said. “Before we even get to clinical trials, we think about how to combine drugs so that the tumors don’t come back. Our results provide evidence to suggest immunotherapy as a partner with KRAS G12D inhibitors.
The researchers were able to assess the impact of MRTX1133 on the immune system because the type of model used in the study allows the tumor to grow spontaneously after implantation in otherwise healthy mice, making it possible to discern the impact of the drug on the surrounding tumor microenvironment (TME).
MRTX1133 selectively inhibits KRASG12D and downstream MAPK signaling in vitro. MRTX1133 dose response of BxPC-3 (KRASWT), AsPC-1 (KRASG12D) and MIA PaCa-2 (KRASG12C) cells after 72 h of treatment. Serial 3-fold dilutions were used and cell viability was measured with CellTiter-Glo. IC50 values are listed. (CREDIT: Cancer Discovery)
The immunocompetent KPC model was developed by Penn Medicine nearly 20 years ago and is the gold standard used worldwide to evaluate potential therapies for pancreatic ductal adenocarcinoma (PDAC). PDAC is known to have a particularly dense TME, which contributes to treatment resistance.
The research team found that the drug caused an increase in T cells in the TME, which improved the depth and duration of the response to MRTX1133. All of the complete remissions seen in the study were accompanied by T cell-mediated anti-tumor immunity.
MRTX1133 selectively inhibits KRASG12D and downstream MAPK signaling in vitro. Representative western blot of cell lysates of 6419c5 (KRASG12D) cells treated with the MRTX1133 control or DMSO for two hours. Representative western blot of cell lysates of BxPC-3 (KRAS-WT) cells treated with the MRTX1133 control or DMSO for two hours. MRTX1133 dose-response of 4662-KRASG12D and 4662-KRASG12C after 72h of treatment. Serial dilutions of 5 times were used. IC50 values are listed (CREDIT: Cancer Discovery)
In mice without T cells, the effect of MRTX1133 was brief and tumors regenerated much faster. These results suggest that MRTX1133 could be combined with immunotherapy to improve long-term response to treatment and prevent cancer recurrence.
“After many years of working to find new, much-needed approaches for pancreatic cancer patients, it’s exciting to have a new class of drugs on the horizon,” said co-corresponding author Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center and John H. Glick Abramson Cancer Center professor at the Perelman School of Medicine, whose lab members worked with those in Stanger’s lab in a cooperative team focused on this study. “We are optimistic that KRAS G12D the inhibitors will soon make their way into clinical trials. kras surrenders, and now we know the immune system can see it.
MRTX1133 is selective for KRASG12D in immunocompetent implantation tumor models. Cascade plot of tumors treated with vehicle and MRTX1133 (6419c5, subcutaneous) showing change in tumor volume after 7 days of treatment compared to baseline at day 0. Each bar represents a single tumor. n = 10 mice/group. (CREDIT: Cancer Discovery)
The study was supported by the National Institutes of Health (R01-CA229803, R01-CA252225, T32-CA009140 and P30-CA016520), Cancer Research Institute (CRI4097), Parker Institute for Cancer
Immunotherapy, the Penn Pancreatic Cancer Research Center and the Abramson Family Cancer Research Institute.
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Note: The documents provided above by UPenn School of Medicine. Content may be edited for style and length.
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