Targeting acquired resistance to KRAS G12C inhibition

KRAS is one of the most commonly altered genes in human cancers, affecting approximately 20% of all cancer patients. KRAS alterations are most frequently observed in cancers of the pancreas, colon, and lung, which together account for more than one-third of all cancer-related deaths in the Western world. Until recently, efforts to directly target KRAS with drugs had been unsuccessful. However, advancements in molecular cancer biology and rapidly evolving drug development techniques have led to the groundbreaking development of KRAS G12C inhibitors. These drugs specifically target a mutation in the KRAS gene present in approximately 3% of all cancer patients. KRAS G12C inhibitors are already in clinical use and have demonstrated to prevent tumor growth and prolong survival in patients. Nevertheless, the clinical benefits of these drugs are often temporary, as tumors sooner or later develop resistance. This underscores the urgent need to better understand the mechanisms of resistance and to identify strategies to overcome it. Our research project is dedicated to addressing this challenge and finding potential solutions to overcome resistance to KRAS G12C inhibitors. We will specifically focus on discovering how new molecular alterations in tumors, which arise during treatment, limit the effectiveness of these drugs. To achieve this, we will analyze blood samples from patients who initially responded to KRAS G12C inhibitors but later experienced disease progression. This will allow us to evaluate the frequency and diversity of newly acquired genomic alterations that may cause drug resistance in patients. In the next phase, we will develop laboratory models of cancer cells and mouse models engineered to mimic the genetic profiles observed in patients who stopped responding to treatment. Using these models, we aim to deepen our understanding of the mechanisms underlying resistance and identify potential vulnerabilities that could be targeted with new drug treatments. Finally, we plan to use this information to develop potential treatment strategies capable of targeting and overcoming these mechanisms of resistance. To achieve this, we will expose our resistant cancer cell models to a range of novel KRAS inhibitors, including various drug combinations. This approach will allow us to investigate whether using drugs that attack cancer cells through different mechanisms can prevent resistance when administered together. The ultimate goal of this project is to generate findings that can guide the clinical development of new and more effective treatment strategies. These strategies aim to target not only KRAS G12C but also other RAS mutations, with the potential to benefit an estimated 3 million patients worldwide who have RAS-mutant cancers.

KRAS is one of the most frequently altered genes in cancer, affecting approximately 20% of all patients with cancer. These mutations are particularly common in pancreatic, colorectal, and lung cancers, which together account for more than one third of cancer-related deaths in the Western world. The development of mutation-specific KRAS G12C inhibitors has, for the first time, made it possible to offer targeted treatments for these tumors. However, despite initial clinical success, most patients develop resistance to therapy within a few months. Our goal was to better understand the genetic mechanisms by which tumor cells escape these drugs. In a comprehensive analysis of blood samples from patients treated with KRAS G12C inhibitors, we found that 46% of patients developed new genetic alterations during treatment that were responsible for loss of drug efficacy. Using laboratory experiments in cancer cell models, we were able to show that novel KRAS inhibitors currently being tested in clinical trials can overcome these resistance mechanisms. Our research therefore provides important insights for the development of more effective treatment strategies for KRAS-mutant cancers, with the potential to benefit an estimated 3 million patients worldwide living with RAS-mutant malignancies.