Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies

by Selleckchem | Aug 30 2023

KRAS, a predominant member of the RAS family, is the most frequently mutated oncogene in human pancreatic cancer (∼95% of cases). Mutations in KRAS lead to its constitutive activation and activation of its downstream signaling pathways such as RAF/MEK/ERK and PI3K/AKT/mTOR that promote cell proliferation and provide apoptosis evasion capabilities to cancer cells. KRAS had been considered 'undruggable' until the discovery of the first covalent inhibitor targeting the G12C mutation. While G12C mutations are frequently found in non-small cell lung cancer, these are relatively rare in pancreatic cancer. On the other hand, pancreatic cancer harbors other KRAS mutations such as G12D and G12V. The inhibitors targeting G12D mutation (such as MRTX1133) have been recently developed, whereas those targeting other mutations are still lacking. Unfortunately, KRAS inhibitor monotherapy-associated resistance hinders their therapeutic efficacy. Therefore, various combination strategies have been tested and some yielded promising results, such as combinations with receptor tyrosine kinase, SHP2, or SOS1 inhibitors. In addition, we recently demonstrated that the combination of sotorasib with DT2216 (a BCL-XL-selective degrader) synergistically inhibits G12C-mutated pancreatic cancer cell growth in vitro and in vivo. This is in part because KRAS-targeted therapies induce cell cycle arrest and cellular senescence, which contributes to therapeutic resistance, while their combination with DT2216 can more effectively induce apoptosis. Similar combination strategies may also work for G12D inhibitors in pancreatic cancer. This chapter will review KRAS biochemistry, signaling pathways, different mutations, emerging KRAS-targeted therapies, and combination strategies. Finally, we discuss challenges associated with KRAS targeting and future directions, emphasizing pancreatic cancer.

Comments:

KRAS is a highly significant oncogene in pancreatic cancer, with mutations occurring in approximately 95% of cases. These mutations result in the constitutive activation of KRAS and its downstream signaling pathways, such as RAF/MEK/ERK and PI3K/AKT/mTOR. Consequently, cell proliferation is promoted, and cancer cells acquire capabilities to evade apoptosis. Initially, KRAS was considered "undruggable," but the discovery of the first covalent inhibitor targeting the G12C mutation brought about a breakthrough. However, G12C mutations are more commonly found in non-small cell lung cancer than in pancreatic cancer. Pancreatic cancer, on the other hand, frequently harbors other KRAS mutations, such as G12D and G12V. While inhibitors targeting the G12D mutation, like MRTX1133, have recently been developed, there is still a lack of inhibitors for other mutations.

Unfortunately, monotherapy with KRAS inhibitors often leads to resistance, which diminishes their therapeutic effectiveness. To overcome this challenge, various combination strategies have been explored, some of which have shown promising results. These strategies involve combining KRAS inhibitors with inhibitors targeting receptor tyrosine kinases, SHP2, or SOS1. Additionally, recent research has demonstrated the synergistic inhibition of G12C-mutated pancreatic cancer cell growth, both in vitro and in vivo, through the combination of sotorasib (a KRAS inhibitor) with DT2216 (a BCL-XL-selective degrader). This combination is effective because KRAS-targeted therapies induce cell cycle arrest and cellular senescence, which contribute to therapeutic resistance, whereas their combination with DT2216 can more effectively induce apoptosis. Similar combination approaches may also prove successful for G12D inhibitors in pancreatic cancer.

In this chapter, we will review the biochemistry of KRAS, its signaling pathways, the different mutations that occur, emerging KRAS-targeted therapies, and the various combination strategies that have been investigated. Additionally, we will discuss the challenges associated with targeting KRAS and outline future directions, with a focus on pancreatic cancer.