International Journal of Molecular Medical Science, 2024, Vol.14, No.5, 305-314 http://medscipublisher.com/index.php/ijmms 309 pathways, such as PI3K signaling, to sustain tumor growth even in the absence of KRAS function. These challenges underscore the need for innovative approaches to effectively target KRAS in pancreatic cancer. 5.3 Emerging therapies and clinical trials Recent advancements have led to the development of novel therapies targeting KRAS mutations. Covalent inhibitors of KRASG12C have shown early promise in clinical trials, offering a new avenue for treatment. Additionally, combination therapies that target multiple pathways simultaneously are being explored. For instance, sequential targeting of TGF-β signaling and KRAS has demonstrated increased therapeutic efficacy in preclinical models. Immunotherapies and tumor vaccines targeting KRAS are also under investigation, with several approaches currently in clinical development (Cowzer et al., 2022). These emerging therapies hold potential for improving outcomes in patients with KRAS-mutant pancreatic cancer. 5.4 Case study: success and challenges of specific KRAS inhibitors A notable case study involves the development and clinical testing of KRASG12C inhibitors. These inhibitors have shown promising results in early-phase clinical trials, demonstrating the potential to effectively target KRAS-mutant pancreatic cancer. However, the success of these inhibitors has been tempered by the emergence of resistance mechanisms. For example, Muzumdar et al. (2017) model complete KRAS inhibition using CRISPR/Cas-mediated genome editing and demonstrate that KRAS is dispensable in a subset of PDAC cells. pancreatic cancer cells can bypass KRAS inhibition by activating alternative signaling pathways, such as PI3K, which underscores the complexity of targeting KRAS in this malignancy (Figure 3; Figure 4). This case study highlights both the potential and the challenges of developing specific KRAS inhibitors for pancreatic cancer treatment. 6 Resistance Mechanisms and Overcoming Challenges 6.1 Mechanisms of resistance to KRAS-targeted therapies Resistance to KRAS-targeted therapies in pancreatic cancer can arise through various mechanisms. Secondary mutations in the KRAS gene itself are a significant cause of acquired resistance. For instance, secondary mutations such as Y96D/S, G13D, R68M, and A59S/T have been identified in resistant clones, which can render KRAS inhibitors like sotorasib and adagrasib ineffective (Koga et al., 2021). Additionally, bypass mechanisms involving other oncogenic pathways, such as MET amplification and mutations in NRAS, BRAF, MAP2K1, and RET, have also been observed, leading to reactivation of the RAS-MAPK signaling pathway (Awad et al., 2021). These diverse genomic alterations highlight the complexity of resistance mechanisms and the need for comprehensive strategies to address them. 6.2 Combination therapies and novel approaches To overcome resistance to KRAS-targeted therapies, combination therapies and novel approaches are being explored. One promising strategy involves the use of SOS1 inhibitors in combination with MEK inhibitors, which has shown potent activity against certain resistant KRAS mutations (Lyu et al., 2022). Additionally, targeting epigenetic vulnerabilities in resistant clones has emerged as a potential approach. For example, combining BET inhibitors with KRAS inhibitors has demonstrated efficacy in preclinical models of pancreatic cancer. Sequential targeting of the TGF-β signaling pathway and KRAS mutations has also been proposed to enhance therapeutic efficacy by dismantling the tumor microenvironment and directly targeting oncogenic KRAS (Pei et al., 2019). These combination strategies aim to address the multifaceted nature of resistance and improve treatment outcomes for pancreatic cancer patients. 6.3 Case study: overcoming resistance in pancreatic cancer patients A notable case study involves the use of a novel KRAS switch-II pocket mutation inhibitor, RM-018, to overcome resistance in a patient with KRASG12C-mutant non-small cell lung cancer who developed resistance to adagrasib. The patient exhibited multiple resistance alterations, including a novel KRASY96D mutation, which interfered with the binding of KRASG12C inhibitors. To understand the significance of the acquired KRASY96D mutation, Tanaka et al. (2021) performed structural modeling of the G12C-mutant and G12C/Y96D double-mutant KRAS proteins bound to the KRASG12C inhibitors MRTX849, AMG 510, and ARS-1620 (Figure
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