KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges

Ceddia, Serena; Landi, Lorenza; Cappuzzo, Federico

doi:10.3390/ijms23169391

Cited by 22 publications

(19 citation statements)

References 86 publications

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“…First, it represents a very up-to-date article about the clinical efficacy of KRAS inhibitors, including the most recent trials results. This is particularly remarkable if we consider that the last review on this topic dates back to August 2022 and that the treatment scenario rapidly evolved since then [ 134 ]. Secondarily, many previous reports alternatively focused on specific aspects within this topic, such as mechanisms of resistance rather than therapeutic agents’ efficacy [ 135 , 136 , 137 ], leaving behind some other important factors that should have been conversely considered.…”

Section: Discussionmentioning

confidence: 99%

KRAS in NSCLC: State of the Art and Future Perspectives

Cascetta

Marinello

Lazzari

et al. 2022

Cancers

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In NSCLC, KRAS mutations occur in up to 30% of all cases, most frequently at codon 12 and 13. KRAS mutations have been linked to adenocarcinoma histology, positive smoking history, and Caucasian ethnicity, although differences have been described across KRAS mutational variants subtypes. KRAS mutations often concur with other molecular alterations, notably TP53, STK11, and KEAP1, which could play an important role in treatment efficacy and patient outcomes. For many years, KRAS mutations have been considered undruggable mainly due to a high toxicity profile and low specificity of compounds. Sotorasib and adagrasib are novel KRAS inhibitors that recently gained FDA approval for pre-treated KRAS mutant NSCLC patients, and other molecules such as GDC-6036 are currently being investigated with promising results. Despite their approval, the efficacy of these drugs is lower than expected and progression among responders has been reported. Mechanisms of acquired resistance to anti-KRAS molecules typically involves either on target secondary mutations (e.g., G12, G13, Q61H, R68S, H95, Y96C, V8L) or off-target alterations. Ongoing trials are currently evaluating strategies for implementing efficacy and overcoming acquired resistance to these compounds. Finally, the efficacy of immune-checkpoint inhibitors still needs to be completely assessed and responses to anti-PD-1/PD-L1 agents may strongly depend on concomitant mutations.

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Section: Discussionmentioning

confidence: 99%

KRAS in NSCLC: State of the Art and Future Perspectives

Cascetta

Marinello

Lazzari

et al. 2022

Cancers

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“…Another study of metastatic CRC showed that the regression of the KRAS mutation was associated with a better prognosis and oligo-metastatic status [ 21 ]. In NSCLC, KRAS mutations are seen in about 30% of lung adenocarcinomas and 5% of squamous lung cancers, in 26% of Westerners and 11% of Asians, and also in 30% of smokers and 10% of nonsmokers [ 22 ]. A study of lung adenocarcinoma patients found that KRAS mutations were significantly associated with older age (>45 years old) at diagnosis [ 23 ].…”

Section: Kras Mutations In Cancersmentioning

confidence: 99%

“…Albuminpaclitaxel combined with gemcitabine is a first-line chemotherapy regimen that has been widely applied to pancreatic cancer, but most patients rapidly develop drug resistance after several courses of treatment [ 61 ]. The average OS of NSCLC patients with KRAS mutations treated with chemotherapy is less than 2 years [ 22 ]. The efficacy of conventionally applied chemotherapy for patients with KRAS mutations is limited and needs to be improved.…”

Section: Therapeutic Strategies In Kras-mutant Cancersmentioning

confidence: 99%

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

Yang

Zhang

Huang

et al. 2023

JCM

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Kristen rat sarcoma (KRAS) gene is one of the most common mutated oncogenes in solid tumors. Yet, KRAS inhibitors did not follow suit with the development of targeted therapy, for the structure of KRAS has been considered as being implausible to target for decades. Chemotherapy was the initial recommended therapy for KRAS-mutant cancer patients, which was then replaced by or combined with immunotherapy. KRAS G12C inhibitors became the most recent breakthrough in targeted therapy, with Sotorasib being approved by the Food and Drug Administration (FDA) based on its significant efficacy in multiple clinical studies. However, the subtypes of the KRAS mutations are complex, and the development of inhibitors targeting non-G12C subtypes is still at a relatively early stage. In addition, the monotherapy of KRAS inhibitors has accumulated possible resistance, acquiring the exploration of combination therapies or next-generation KRAS inhibitors. Thus, other non-target, conventional therapies have also been considered as being promising. Here in this review, we went through the characteristics of KRAS mutations in cancer patients, and the prognostic effect that it poses on different therapies and advanced therapeutic strategy, as well as cutting-edge research on the mechanisms of drug resistance, tumor development, and the immune microenvironment.

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“…Nevertheless, because of the particularity of the KRAS protein structure, there is no effective drug to treat KRAS mutant tumours thus far. Epidermal growth factor receptor (EGFR) is the upstream signalling pathway of KRAS [ 144 , 145 ]. Through the study of targeted EGFR inhibitors, the upstream signalling pathway can be blocked to block the mutant expression of KRAS.…”

Section: Modulation Of Cell Death In Hnsccmentioning

confidence: 99%

Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma

et al. 2023

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Head and neck cancer is a malignant tumour with a high mortality rate characterized by late diagnosis, high recurrence and metastasis rates, and poor prognosis. Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancer. Various factors are involved in the occurrence and development of HNSCC, including external inflammatory stimuli and oncogenic viral infections. In recent years, studies on the regulation of cell death have provided new insights into the biology and therapeutic response of HNSCC, such as apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and recently the newly discovered cuproptosis. We explored how various cell deaths act as a unique defence mechanism against cancer emergence and how they can be exploited to inhibit tumorigenesis and progression, thus introducing regulatory cell death (RCD) as a novel strategy for tumour therapy. In contrast to accidental cell death, RCD is controlled by specific signal transduction pathways, including TP53 signalling, KRAS signalling, NOTCH signalling, hypoxia signalling, and metabolic reprogramming. In this review, we describe the molecular mechanisms of nonapoptotic RCD and its relationship to HNSCC and discuss the crosstalk between relevant signalling pathways in HNSCC cells. We also highlight novel approaches to tumour elimination through RCD.

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KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges

Cited by 22 publications

References 86 publications

KRAS in NSCLC: State of the Art and Future Perspectives

KRAS in NSCLC: State of the Art and Future Perspectives

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma

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