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.