Drugging the undruggable: Advances in targeting KRAS signaling in solid tumors

Cancer remains the leading cause of global mortality, prompting a paradigm shift in its treatment and outcomes with the advent of targeted therapies. Among the most prevalent mutations in RAS-driven cancers, Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations account for approximately 86% of cases worldwide, particularly in lung, pancreatic, and colon cancers, contributing to poor prognosis and reduced overall survival. Despite numerous efforts to understand the biology of KRAS mutants and their pivotal role in cancer development, the lack of well-defined drug-binding pockets has deemed KRAS an “undruggable” therapeutic target, presenting significant challenges for researchers and clinicians alike. Through significant biochemical and technological advances, the last decade has witnessed promising breakthroughs in targeted therapies for KRAS-mutated lung, colon, and pancreatic cancers, marking a critical turning point in the field. In this chapter, we provide an overview of the characteristics of KRAS mutations across various solid tumors, highlighting ongoing cutting-edge research on the immune microenvironment, the development of KRAS-driven mice models, and the recent progress in the exploration of specific KRAS mutant-targeted therapeutic approaches. By comprehensive understanding of the intricacies of KRAS signaling in solid tumors and the latest therapeutic developments, this chapter will shed light on the potential for novel therapeutic strategies to combat KRAS-driven tumors and improve patient outcomes.