1 Introduction

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), is one of the most lethal malignancies, with a dismal prognosis and a five-year survival rate of less than 10% (Buscail et al., 2020). Despite advancements in diagnostic techniques and therapeutic regimens, the mortality rate remains high, and PDAC is projected to become the second leading cause of cancer-related deaths within the next decade. The aggressive nature of this disease is attributed to its late presentation, rapid progression, and resistance to conventional therapies (Voutsadakis and Digklia, 2023).

A hallmark of pancreatic cancer is the high prevalence of oncogenic mutations in the KRAS gene, which are present in approximately 90~95% of PDAC cases (Waters and Der, 2018). These mutations lead to the constitutive activation of the KRAS protein, which in turn drives multiple intracellular signaling pathways that promote tumorigenesis, including cell proliferation, migration, and survival. The KRAS mutation is not only a critical driver of pancreatic cancer but also a significant factor in its poor prognosis and therapeutic resistance (Luo, 2021). Recent studies have highlighted the potential of targeting KRAS and its downstream effectors as a therapeutic strategy, although effective inhibitors have yet to be successfully translated into clinical practice (Bryant et al., 2014).

This study aims to provide a comprehensive analysis of the genomic mechanisms and therapeutic implications of KRAS mutations in pancreatic cancer. The study will cover the detection methods for KRAS mutations, the impact of these mutations on patient outcomes, and the potential for personalized treatment approaches based on KRAS status. By synthesizing current research findings, the study hope to elucidate the role of KRAS in the pathogenesis of PDAC, explore the diagnostic and prognostic value of KRAS mutations, evaluate emerging therapeutic strategies targeting KRAS and its associated pathways, and hope to contribute to the ongoing efforts to improve the management and treatment of pancreatic cancer.

2 KRAS Gene and Its Role in Cancer

2.1 Structure and function of the KRAS gene

The KRAS gene is a member of the RAS gene family, which also includes HRAS and NRAS. These genes encode small GTPase proteins that act as molecular switches, cycling between an active GTP-bound state and an inactive GDP-bound state. The KRAS protein plays a crucial role in regulating cell proliferation, differentiation, and survival by transmitting signals from cell surface receptors to intracellular signaling pathways such as the MAPK and PI3K pathways (Buscail et al., 2020). The structure of KRAS includes a G-domain responsible for GTP/GDP binding and intrinsic GTPase activity, and a hypervariable region that undergoes post-translational modifications essential for membrane localization and function (Hunter et al., 2015).

2.2 Mechanisms of KRAS activation in cancer

KRAS activation in cancer typically occurs through point mutations that result in the protein being constitutively active, meaning it is always in the GTP-bound state and continuously signals downstream pathways regardless of external stimuli. The most common mutations occur at codons 12, 13, and 61, which impair the GTPase activity of KRAS, preventing the hydrolysis of GTP to GDP and thus locking KRAS in its active form. This persistent activation leads to uncontrolled cell proliferation, survival, and metastasis. Additionally, KRAS mutations can cooperate with other genetic alterations, such as TP53 mutations, to enhance tumorigenic processes (Kim et al., 2021).

2.3 Common KRAS mutations in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a near-universal presence of KRAS mutations, with over 90% of cases exhibiting these alterations (Waters and Der, 2018). The most prevalent mutation in PDAC is KRASG12D, followed by KRASG12V and KRASG12R. These mutations lead to the constitutive activation of KRAS, driving the initiation and maintenance of pancreatic tumors (Luo, 2021). The specific biochemical properties of these mutations, such as altered nucleotide exchange kinetics and interactions with downstream effectors like RAF kinase, contribute to the aggressive nature of PDAC. Furthermore, the presence of KRAS mutations is associated with poor prognosis and resistance to conventional therapies, highlighting the need for targeted therapeutic strategies (Bournet et al., 2016; Tímár and Kashofer, 2020).

3 Genomic Mechanisms of KRAS Mutations in Pancreatic Cancer

3.1 Molecular pathways affected by KRAS mutations

KRAS mutations, particularly the KRASG12D variant, play a pivotal role in pancreatic cancer by activating several molecular pathways that drive tumorigenesis. Oncogenic KRAS upregulates Hedgehog signaling, inflammatory pathways, and pathways mediating paracrine interactions between epithelial cells and their microenvironment, which are crucial for the formation and maintenance of the fibroinflammatory stroma in pancreatic cancer (Collins et al., 2012). Additionally, KRAS mutations lead to the permanent activation of the P21 RAS protein, triggering a cascade of signaling pathways that promote cellular transformation, proliferation, invasion, and survival (Bournet et al., 2016). The NF-κB pathway is also significantly influenced by KRAS mutations, with GSK-3α stabilizing the TAK1-TAB complex to promote IKK activity and noncanonical NF-κB signaling, which are essential for pancreatic cancer cell growth and survival (Bang et al., 2013).

3.2 Interaction with other oncogenes and tumor suppressor genes

KRAS mutations often co-occur with alterations in other oncogenes and tumor suppressor genes, such as TP53. In pancreatic ductal adenocarcinoma (PDAC), KRAS mutations are present in 95% of tumors, and TP53 mutations co-occur in nearly 70% of cases. This interaction leads to the activation of pro-metastatic transcriptional networks through the cooperation of mutant p53 and KRAS effectors, such as CREB1, which upregulates FOXA1 and promotes Wnt/β-catenin signaling, driving metastasis (Kim et al., 2021). Furthermore, the ARF6-AMAP1 pathway is a major target of KRAS and TP53 mutations, promoting tumor invasion and immune evasion by regulating integrin and E-cadherin dynamics (Hashimoto et al., 2019). These interactions highlight the complex interplay between KRAS and other genetic alterations in driving pancreatic cancer progression.

3.3 Impact on cellular processes

KRAS mutations significantly impact various cellular processes, including proliferation, apoptosis, and metastasis. Oncogenic KRAS induces mitochondrial oxidative stress in pancreatic acinar cells, leading to increased generation of mitochondrial reactive oxygen species (mROS). This oxidative stress drives the dedifferentiation of acinar cells to a duct-like progenitor phenotype and progression to pancreatic intraepithelial neoplasia (PanIN) through the upregulation of epidermal growth factor signaling (Liou et al., 2016). Additionally, KRAS mutations promote NIX-mediated mitophagy, which restricts glucose flux to the mitochondria and enhances redox capacity, thereby supporting glycolysis and disease progression (Humpton et al., 2019). The suppression of metastasis-related genes by KRAS also underscores its role in regulating cellular processes critical for tumor growth and dissemination (Muzumdar et al., 2017). Collectively, these mechanisms illustrate how KRAS mutations orchestrate a range of cellular activities to facilitate pancreatic cancer development and metastasis.

4 Detection and Analysis of KRAS Mutations

4.1 Techniques for detecting KRAS mutations

Detecting KRAS mutations in pancreatic cancer is crucial for diagnosis, prognosis, and treatment planning. Several advanced techniques have been developed to identify these mutations in various biological samples. Quantitative polymerase chain reaction (qPCR) is a reliable method for assessing KRAS mutations in tissue samples and fine-needle aspiration biopsies. Digital droplet PCR (ddPCR) is another highly sensitive technique that can detect KRAS mutations in biological samples, including serum and plasma (liquid biopsies) (Buscail et al., 2020). Additionally, chip-based digital PCR has shown promise in detecting KRAS mutations in circulating tumor DNA (ctDNA) from early-stage pancreatic cancer patients (Brychta et al., 2016). Multiplex digital PCR on a droplet array SlipChip is a novel method that allows for the precise quantification of multiple KRAS mutations, providing a robust tool for both research and clinical diagnostics (Hu et al., 2022).

4.2 Diagnostic significance and prognostic value

The presence of KRAS mutations in pancreatic cancer has significant diagnostic and prognostic implications. Combining KRAS mutation assays with endoscopic ultrasound-guided cytopathology enhances the sensitivity, accuracy, and negative predictive value of cytopathology alone, improving the positive diagnosis of pancreatic cancer and its differentiation from benign conditions. KRAS mutations are detected in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases and are associated with a worse prognosis, both in advanced and resected tumors (Bournet et al., 2016; Ardalan et al., 2023). The concentration and fractional abundance of KRAS mutations in cfDNA are significant factors for progression-free survival and overall survival, making them valuable prognostic biomarkers (Kim et al., 2018). Interestingly, KRAS wild-type status, as detected by circulating tumor DNA analysis, may be associated with better clinical outcomes and could serve as a prognostic or predictive factor for treatment response (Teufel et al., 2015).

4.3 Case study: application of KRAS mutation analysis in clinical settings

A notable case study involves the application of KRAS mutation analysis in a clinical trial for patients with locally advanced pancreatic cancer (LAPC) treated with gefitinib and chemoradiation therapy. In this study, plasma KRAS mutations were monitored at multiple time points to assess disease progression and treatment response. The clearance or persistence of plasma KRAS mutations after treatment correlated with patient outcomes, demonstrating the potential of KRAS mutation analysis as a marker for survival and response to therapy (Chen et al., 2006). Another study evaluated the clinical applicability of multiplex detection of KRAS mutations in cfDNA from patients with PDAC. The findings indicated that higher concentrations of KRAS mutations in cfDNA were associated with poorer clinical outcomes (Figure 1; Figure 2), reinforcing the prognostic value of KRAS mutation analysis in managing pancreatic cancer (Kim et al., 2018).

5 Therapeutic Implications of KRAS Mutations

5.1 Current treatment strategies targeting KRAS mutations

KRAS mutations are a hallmark of pancreatic cancer, present in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases (Luo, 2021). Current treatment strategies have focused on targeting the KRAS signaling pathway through various approaches. These include the development of covalent inhibitors targeting specific KRAS mutations, such as KRAS^G12C, which have shown promising activity in early clinical trials. Additionally, efforts have been made to inhibit downstream effectors of KRAS, such as the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways (Bournet et al., 2016; Bannoura et al., 2021). Despite these efforts, the clinical efficacy of these inhibitors has been limited, necessitating the exploration of novel therapeutic strategies.

5.2 Challenges in developing KRAS-targeted therapies

Developing effective KRAS-targeted therapies has been fraught with challenges. One major obstacle is the "undruggable" nature of KRAS, which has made direct inhibition difficult (Waters and Der, 2018). Additionally, the tumor microenvironment in pancreatic cancer poses significant barriers to drug delivery and efficacy (Pei et al., 2019). Resistance mechanisms also play a critical role, as pancreatic cancer cells can activate compensatory 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 KRAS^G12C 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 KRAS^G12C 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 KRAS^G12C-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 KRAS^G12C 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 5). This case underscores the potential of developing next-generation inhibitors that can target specific resistance mutations and highlights the importance of personalized treatment strategies in managing resistance in pancreatic cancer patients.

7 Future Directions and Perspectives

7.1 Advances in genomic technologies for better understanding KRAS mutations

The advent of advanced genomic technologies has significantly enhanced our understanding of KRAS mutations in pancreatic cancer. Techniques such as digital droplet PCR and next-generation sequencing (NGS) have improved the sensitivity and accuracy of detecting KRAS mutations in various biological samples, including fine-needle aspiration materials and liquid biopsies (Buscail et al., 2020). These technologies not only facilitate early and precise diagnosis but also enable the monitoring of tumor dynamics and treatment responses through longitudinal assessments of circulating tumor DNA (ctDNA). Future research should focus on refining these technologies to further increase their sensitivity and specificity, as well as integrating multi-omics approaches to provide a comprehensive understanding of the molecular landscape of KRAS-mutant pancreatic cancer.

7.2 Potential biomarkers for predicting therapy response

Identifying reliable biomarkers for predicting therapy response in KRAS-mutant pancreatic cancer remains a critical area of research. Studies have shown that the presence of specific KRAS mutations, such as G12D and G12V, can influence the efficacy of targeted therapies and chemotherapy (Hamidi et al., 2013). Additionally, the detection of KRAS mutations in ctDNA has been associated with prognosis and therapeutic outcomes, suggesting its potential as a predictive biomarker (Watanabe et al., 2019). Other molecular alterations, such as copy number variations and mutations in alternative MAPK pathway drivers, have also been identified as potential biomarkers for therapy response in KRAS wild-type pancreatic cancer (Singh) (Kato et al., 2023). Future research should aim to validate these biomarkers in larger clinical cohorts and explore their utility in guiding personalized treatment strategies.

7.3 Personalized medicine approaches for KRAS-Mutant pancreatic cancer

Personalized medicine approaches hold promise for improving the treatment outcomes of patients with KRAS-mutant pancreatic cancer. Targeting KRAS directly has been challenging, but recent advances in the development of covalent inhibitors targeting specific KRAS mutations, such as KRAS^G12C, have shown promising results in early clinical trials (Luo, 2021). Additionally, targeting downstream effectors of the KRAS signaling pathway, such as MEK and ERK, has demonstrated potential in preclinical and clinical studies (Teufel et al., 2015). Combining these targeted therapies with standard chemotherapy or other novel agents may enhance their efficacy and overcome resistance mechanisms. Future research should focus on optimizing these combination therapies and developing robust clinical trials to evaluate their effectiveness in diverse patient populations.

8 Concluding Remarks

KRAS mutations are key drivers of pancreatic ductal adenocarcinoma (PDAC), present in over 90% of cases. This paper reviews the genomic mechanisms of KRAS mutations in pancreatic cancer and their impact on tumor initiation, progression, and therapeutic resistance. KRAS mutations promote tumor cell proliferation, invasion, and survival by activating multiple signaling pathways, such as MAPK and PI3K. Furthermore, the interaction between KRAS mutations and other oncogenes and tumor suppressor genes exacerbates the aggressiveness of pancreatic cancer and its resistance to treatment. Although significant progress has been made in detecting and analyzing KRAS mutations, effective KRAS-targeted therapies still face considerable challenges.

The high prevalence of KRAS mutations and their decisive role in pancreatic cancer progression make them critical biomarkers for diagnosis, prognosis, and treatment decision-making. The detection of KRAS mutations in liquid biopsies, particularly in circulating tumor DNA, has shown potential in monitoring disease progression and treatment response. In clinical treatment, despite some progress in KRAS-targeted therapies, resistance issues remain, indicating the need for new therapies and combination strategies to overcome these challenges. Future research should further explore the relationship between KRAS mutations and other molecular alterations to identify new therapeutic targets and biomarkers, thereby optimizing personalized treatment strategies.

Although KRAS has been considered an "undruggable" target, recent studies have brought new hope for the development of KRAS-targeted therapies. The development and clinical trial results of KRAS^G12C inhibitors have shown potential, particularly in patients with specific KRAS mutations. However, the heterogeneity of KRAS mutations and the complexity of the tumor microenvironment continue to pose challenges for treatment. Future research directions include developing next-generation inhibitors targeting resistance mutations and exploring combination therapies to enhance efficacy. Additionally, leveraging the potential of immunotherapies and tumor vaccines may offer new treatment options for patients with KRAS-mutant pancreatic cancer. With the continuous advancement of genomic technologies and a deeper understanding of KRAS-related molecular mechanisms, KRAS-targeted therapies are expected to play a more pivotal role in the treatment of pancreatic cancer.

Acknowledgments

The authors extend sincere thanks to two anonymous peer reviewers for their feedback on the manuscript of this study.

Funding

This study is supported by the Fujian Natural Science Foundation [grant number: 2023J01755] project.

Conflict of Interest Disclosure

The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

References

Ardalan B., Ciner A., Baca Y., Darabi S., Kasi A., Lou E., Azqueta J., Xiu J., Nabhan C., Shields A., Pishvaian M., Korn W., and Goel S., 2023, Prognostic indicators of KRAS G12X mutations in pancreatic cancer, Journal of Clinical Oncology, 41(4): 735. 

https://doi.org/10.1200/jco.2023.41.4_suppl.735.

Awad M., Liu S., Rybkin I., Arbour K., Dilly J., Zhu V., Johnson M., Heist R., Patil T., Riely G., Jacobson J., Yang X., Persky N., Root D., Lowder K., Feng H., Zhang S., Haigis K., Hung Y., Sholl L., Wolpin B., Wiese J., Christiansen J., Lee J., Schrock A., Lim L., Garg K., Li M., Engstrom L., Waters L., Lawson J., Olson P., Lito P., Ou S., Christensen J., Jänne P., and Aguirre A., 2021, Acquired resistance to KRAS^G12C inhibition in cancer, The New England Journal of Medicine, 384(25): 2382-2393.

https://doi.org/10.1056/NEJMoa2105281

Bang D., Wilson W., Ryan M., Yeh J., and Baldwin A., 2013, GSK-3α promotes oncogenic KRAS function in pancreatic cancer via TAK1-TAB stabilization and regulation of noncanonical NF-κB, Cancer Discovery, 3(6): 690-703.

https://doi.org/10.1158/2159-8290.CD-12-0541

Bannoura S., Uddin M., Nagasaka M., Fazili F., Al-Hallak M., Philip P., El-Rayes B., and Azmi A., 2021, Targeting KRAS in pancreatic cancer: new drugs on the horizon, Cancer and Metastasis Reviews, 40: 819-835.

https://doi.org/10.1007/s10555-021-09990-2

Bournet B., Buscail C., Muscari F., Cordelier P., and Buscail L., 2016, Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: hopes and realities, EuropeanJournal of Cancer, 54: 75-83.

https://doi.org/10.1016/j.ejca.2015.11.012

Bryant K., Mancias J., Kimmelman A., and Der C., 2014, KRAS: feeding pancreatic cancer proliferation, Trends in Biochemical Sciences, 39(2): 91-100.

https://doi.org/10.1016/j.tibs.2013.12.004

Brychta N., Krahn T., and Ahsen O., 2016, Detection of KRAS mutations in circulating tumor DNA by digital PCR in early stages of pancreatic cancer, Clinical Chemistry, 62(11): 1482-1491.

https://doi.org/10.1373/CLINCHEM.2016.257469

Buscail L., Bournet B., and Cordelier P., 2020, Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer, Nature Reviews Gastroenterology & Hepatology, 17: 153-168.

https://doi.org/10.1038/s41575-019-0245-4

Chen H., Raben D., Schefter T., Kane M., McCarter M., Olsen C., McCoy K., Eckhardt S., and Gumerlock P., 2006, KRAS mutation analysis in patients (pts) with locally advanced pancreatic cancer (LAPC) treated with gefitinib and chemoradiation therapy (CT-RT) in a phase I trial, Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 24 (18): 4106.

https://doi.org/10.1200/JCO.2006.24.18_SUPPL.4106

Collins M., Bednar F., Zhang Y., Brisset J., Galban S., Galbán C., Rakshit S., Flannagan K., Adsay N., and Magliano M., 2012, Oncogenic kras is required for both the initiation and maintenance of pancreatic cancer in mice, The Journal of Clinical Investigation, 122(2): 639-653.

https://doi.org/10.1172/JCI59227

Cowzer D., Zameer M., Conroy M., Kolch W., and Duffy A., 2022, Targeting KRAS in pancreatic cancer, Journal of Personalized Medicine, 12(11): 1870.

https://doi.org/10.3390/jpm12111870

Hamidi H., Finn R., Anderson L., Lu M., Fejzo M., Ginther C., Linnartz R., and Zubel A., 2013, Abstract 936: KRAS mutational subtypes and copy number variations are predictive of response of human pancreatic cancer cell lines to MEK162in vitro, Cancer Research, 73: 936.

https://doi.org/10.1158/1538-7445.AM2013-936

Hashimoto S., Furukawa S., Hashimoto A., Tsutaho A., Fukao A., Sakamura Y., Parajuli G., Onodera Y., Otsuka Y., Handa H., Oikawa T., Hata S., Nishikawa Y., Mizukami Y., Kodama Y., Murakami M., Fujiwara T., Hirano S., and Sabe H., 2019, ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer, Proceedings of the National Academy of Sciences of the United States of America, 116: 17450-17459.

https://doi.org/10.1073/pnas.1901765116

Hu Q., Kanwal F., Lyu W., Zhang J., Liu X., Qin K., and Shen F., 2022, Multiplex digital polymerase chain reaction on a droplet array slipchip for analysis of KRAS mutations in pancreatic cancer, ACS Sensors, 8(1): 114-121.

https://doi.org/10.1021/acssensors.2c01776

Humpton T., Alagesan B., DeNicola G., Lu D., Yordanov G., Leonhardt C., Yao M., Alagesan P., Zaatari M., Park Y., Skepper J., Macleod K., Pérez-Mancera P., Murphy M., Evan G., Vousden K., and Tuveson D., 2019, Oncogenic Kras induces Nix-mediated mitophagy to promote pancreatic cancer, Cancer Discovery, 9(9): 1268-1287.

https://doi.org/10.1158/2159-8290.CD-18-1409

Hunter J., Manandhar A., Carrasco M., Gurbani D., Gondi S., and Westover K., 2015, Biochemical and structural analysis of common cancer-associated KRAS mutations, Molecular Cancer Research, 13: 1325-1335.

https://doi.org/10.1158/1541-7786.MCR-15-0203

Kato H., Ellis H., and Bardeesy N., 2023, KRAS wild-type pancreatic cancer: decoding genomics, unlocking therapeutic potential, Clinical Cancer Research: an Official Journal of the American Association for Cancer Research, 29(22): 4527-4529.

https://doi.org/10.1158/1078-0432.CCR-23-2221

Kim M., Li X., Deng J., Zhang Y., Dai B., Allton K., Hughes T., Siangco C., Augustine J., Kang Y., McDaniel J., Xiong S., Koay E., McAllister F., Bristow C., Heffernan T., Maitra A., Liu B., Barton M., Wasylishen A., Fleming J., and Lozano G., 2021, Oncogenic KRAS recruits an expansive transcriptional network through mutant p53 to drive pancreatic cancer metastasis, Cancer Discovery, 11(8): 2094-2111. 

https://doi.org/10.1158/2159-8290.CD-20-1228

Kim M., Woo S., Park B., Yoon K., Kim Y., Joo J., Lee W., Han S., Park S., and Kong S., 2018, Prognostic implications of multiplex detection of KRAS mutations in cell-free DNA from patients with pancreatic ductal adenocarcinoma, Clinical Chemistry, 64(4): 726-734.

https://doi.org/10.1373/clinchem.2017.283721

Koga T., Suda K., Fujino T., Ohara S., Hamada A., Nishino M., Chiba M., Shimoji M., Takemoto T., Arita T., Gmachl M., Hofmann M., Soh J., and Mitsudomi T., 2021, KRAS secondary mutations that confer acquired resistance to KRAS G12C inhibitors, sotorasib and adagrasib, and overcoming strategies: insights from the in vitro experiments, Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer, 16(8): 1321-1332.

https://doi.org/10.1016/j.jtho.2021.04.015

Liou G., Döppler H., DelGiorno K., Zhang L., Leitges M., Crawford H., Murphy M., and Storz P., 2016, Mutant KRas-induced mitochondrial oxidative stress in acinar cells upregulates EGFR signaling to drive formation of pancreatic precancerous lesions, Cell Reports, 14(10): 2325-2336. 

https://doi.org/10.1016/j.celrep.2016.02.029

Luo J., 2021, KRAS mutation in pancreatic cancer, Seminars in Oncology, 48(1): 10-18.

https://doi.org/10.1053/j.seminoncol.2021.02.003

Lyu H., Minelli R., Deckard C., Seth S., Huang J., Jiang H., Peoples M., Lam M., Bristow C., Gerlach D., Tontsch-Grunt U., Li C., Ho I., Vellano C., Hofmann M., Heffernan T., Marszalek J., Viale A., and Carugo A., 2022, Abstract LB079: pancreatic clonal replica tumors display functional heterogeneity in response to KRAS pharmacological inhibition and reveal unique epigenetic vulnerabilities to overcome resistance, Cancer Research, 82(12): LB079.

https://doi.org/10.1158/1538-7445.am2022-lb079

Muzumdar M., Chen P., Dorans K., Chung K., Bhutkar A., Hong E., Noll E., Sprick M., Trumpp A., and Jacks T., 2017, Survival of pancreatic cancer cells lacking KRAS function, Nature Communications, 8(1): 1090.

https://doi.org/10.1038/s41467-017-00942-5

Pei Y., Chen L., Huang Y., Wang J., Feng J., Xu M., Chen Y., Song Q., Jiang G., Gu X., Zhang Q., Gao X., and Chen J., 2019, Sequential targeting TGF-β signaling and KRAS mutation increases therapeutic efficacy in pancreatic cancer, Small, 15(24): e1900631.

https://doi.org/10.1002/smll.201900631

Singh H., Keller R., Kapner K., Dilly J., Raghavan S., Yuan C., Cohen E., Tolstorukov M., Hill E., Andrews E., Brais L., Silva A., Perez K., Rubinson D., Schlechter B., Rosenthal M., Hornick J., Nardi V., Li Y., Gupta H., Cherniack A., Meyerson M., Cleary J., Nowak J., Wolpin B., and Aguirre A., 2022, Abstract A001: clinical-genomic analysis of KRAS wild-type pancreatic cancer confirms alternative targetable drivers and provides insight for age and risk related clinical stratification, Cancer Research, 82(22): A001. 

https://doi.org/10.1158/1538-7445.panca22-a001

Tanaka N., Lin J., Li C., Ryan M., Zhang J., Kiedrowski L., Michel A., Syed M., Fella K., Sakhi M., Baiev I., Juric D., Gainor J., Klempner S., Lennerz J., Siravegna G., Bar-Peled L., Hata A., Heist R., and Corcoran R., 2021, Clinical acquired resistance to KRAS^G12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation, Cancer Discovery, 11(8): 1913-1922.

https://doi.org/10.1158/2159-8290.CD-21-0365

Teufel M., Laethem J., Riess H., Giurescu M., Garosi V., Schulz A., Vonk R., Seidel H., Reischl J., and Childs B., 2015, Abstract 5239: KRAS wild-type status as detected by circulating tumor DNA analysis may be a prognostic or predictive factor for clinical benefit in patients with unresectable, locally advanced or metastatic pancreatic cancer (PC) treated with the MEK inhibitor refametin, Cancer Research, 75: 5239.

https://doi.org/10.1158/1538-7445.AM2015-5239

Tímár J., and Kashofer K., 2020, Molecular epidemiology and diagnostics of KRAS mutations in human cancer, Cancer Metastasis Reviews, 39: 1029-1038.

https://doi.org/10.1007/s10555-020-09915-5

Voutsadakis I., and Digklia A., 2023, Pancreatic adenocarcinomas without KRAS, TP53, CDKN2A and SMAD4 mutations and CDKN2A/CDKN2B copy number alterations: a review of the genomic landscape to unveil therapeutic avenues, Chinese Clinical Oncology, 12(1): 2.

https://doi.org/10.21037/cco-22-108

Watanabe F., Suzuki K., Tamaki S., Abe I., Endo Y., Takayama Y., Ishikawa H., Kakizawa N., Saito M., Futsuhara K., Noda H., Konishi F., and Rikiyama T., 2019, Longitudinal monitoring of KRAS-mutated circulating tumor DNA enables the prediction of prognosis and therapeutic responses in patients with pancreatic cancer, PLoS ONE, 14(12): e0227366.

https://doi.org/10.1371/journal.pone.0227366

Waters A., and Der C., 2018, KRAS: the critical driver and therapeutic target for pancreatic cancer, Cold Spring Harbor Perspectives in Medicine, 8(9): a031435.

https://doi.org/10.1101/cshperspect.a031435