A small molecule inhibitor that attacks the difficult-to-target, cancer-causing gene mutation KRAS, present in nearly 30 percent of all human tumors, successfully shrunk tumors or stopped cancer growth in preclinical models of pancreatic cancer, researchers from Penn Medicine’s Abramson Cancer Center showed, suggesting the drug is a robust candidate for clinical trials. The study was published today in Cancer Discovery, a journal of the American Association for Cancer Research.

The outcomes of this study are in stark contrast to anything we have seen before in pancreatic cancer. Even in preclinical research models for this cancer type, most drugs tested inside the last decade – including novel immunotherapies – have had limited impact.”

Ben Stanger, MD, PhD, co-corresponding senior writer, the Hanna Sensible Professor in Cancer Research within the Perelman School of Medicine on the University of Pennsylvania and director of the Penn Pancreatic Cancer Research Center

Patients with pancreatic cancer have an overall poor prognosis with a five-year survival rate of 11 percent and limited treatment options. Nearly 90 percent of pancreatic cancers are driven by a mutation within the KRAS gene, probably the most common oncogene across cancer types. The primary targeted therapy for KRAS was approved last yr for non-small cell lung cancer with KRAS G12C mutations, but only 2 percent of pancreatic cancers express that form of mutation. Around 36 percent of pancreatic cancers with a KRAS mutation are KRAS G12D-mutant.

The small molecule inhibitor utilized in this study, MRTX1133 (developed by Mirati Therapeutics) specifically targets KRAS G12D, as the corporate first reported last month in Nature Medicine. The Penn study now shows the KRAS-inhibitor not only directly targets cancer cells but additionally unexpectedly cooperates with the immune system to supply a durable response to treatment, which is very important because cancer eventually finds a option to evade most targeted therapies.

“We all know from KRAS G12C studies and other targeted therapy studies that resistance goes to occur,” Stanger said. “Even before we get to clinical trials, we’re fascinated with tips on how to mix drugs in order that the tumors won’t come back. Our findings provide evidence to suggest immunotherapy as a partner with KRAS G12D inhibitors.”

The researchers were in a position to assess the impact of MRTX1133 on the immune system since the form of model utilized in the study allows the tumor to spontaneously evolve after implantation in otherwise healthy mice, making it possible to discern the drug’s impact on the encompassing tumor microenvironment (TME). 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 understood for having a very dense TME, which contributes to resistance to therapy.

The research team found that the drug prompted a rise of T cells within the TME, which improved the depth and duration of response to MRTX1133. All complete remissions observed within the study were accompanied by T cell mediated anti-tumor immunity. In mice without T cells, the effect of MRTX1133 was temporary and tumors grow back rather more quickly. These results suggest that MRTX1133 may very well be combined with immunotherapy to enhance long-term response to therapy and keep the cancer from returning.

“After a few years of labor to seek out much-needed recent approaches for patients with pancreatic cancer, it’s exciting to have a recent class of medication on the horizon,” said co-corresponding writer Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center and the John H. Glick Abramson Cancer Center Professor within the Perelman School of Medicine, whose lab members worked with those in Stanger’s lab in a focused cooperative team on this study. “We’re optimistic that KRAS G12D inhibitors will make their way into clinical trials soon. KRAS is surrendering, and now we all know the immune system can see it.”

Source:

University of Pennsylvania School of Medicine

Journal reference:

Kemp, S.B., et al. (2022) Efficacy of a small molecule inhibitor of KrasG12D in immunocompetent models of pancreatic cancer. Cancer Discovery. doi.org/10.1158/2159-8290.CD-22-1066.