Targeting KRAS in NSCLC: Old Failures and New Options for “Non-G12c” Patients

Jacobs, Francesca; Cani, Massimiliano; Malapelle, Umberto; Novello, Silvia; Napoli, Valerio Maria; Bironzo, Paolo

doi:10.3390/cancers13246332

Cited by 14 publications

(10 citation statements)

References 108 publications

(122 reference statements)

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“…KRAS mutations are dominant in lung, colorectal, and pancreatic cancers [49] with various types of mutations. G12V mutation [50], carried by Patient #1 in our study, represents around 22% of all KRAS mutations involving the replacement of glycine by valine. In the less common G12D mutation (16%) found [51] in Patient #3, a glycine is replaced by an aspartic acid mutation resulting from a G>A substitution.…”

Section: Discussionmentioning

confidence: 60%

NKp44-Derived Peptide Used in Combination Stimulates Antineoplastic Efficacy of Targeted Therapeutic Drugs

Iraqi

Bolel

Sarkar

et al. 2022

IJMS

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Lung cancer cells in the tumor microenvironment facilitate immune evasion that leads to failure of conventional chemotherapies, despite provisionally decided on the genetic diagnosis of patients in a clinical setup. The current study follows three lung cancer patients who underwent “personalized” chemotherapeutic intervention. Patient-derived xenografts (PDXs) were subjected to tumor microarray and treatment screening with chemotherapies, either individually or in combination with the peptide R11-NLS-pep8; this peptide targets both membrane-associated and nuclear PCNA. Ex vivo, employing PDX-derived explants, it was found that combination with R11-NLS-pep8 stimulated antineoplastic effect of chemotherapies that were, although predicted based on the patient’s genetic mutation, inactive on their own. Furthermore, treatment in vivo of PDX-bearing mice showed an exactly similar trend in the result, corroborating the finding to be translated into clinical setup.

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Section: Discussionmentioning

confidence: 60%

NKp44-Derived Peptide Used in Combination Stimulates Antineoplastic Efficacy of Targeted Therapeutic Drugs

Iraqi

Bolel

Sarkar

et al. 2022

IJMS

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“…KRAS -mutant NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in associated pathways, which should be considered when evaluating the treatment outcome [ 23 ]. At least at the time of diagnosis, KRAS mutations were described to be mutually exclusive with other alterations in NSCLC patients such as EGFR and BRAF mutations, as well as ALK and ROS rearrangements [ 24 ]. However, rare co-occurrence with EGFR (1.2%) and BRAF (1.2%) has been found, and co-occurring mutations with TP53 , PTEN , and STK11 have been described previously [ 21 , 23 , 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Characteristics and Treatment Outcomes in Advanced-Stage Non-Small Cell Lung Cancer Patients with a KRAS G12C Mutation: A Real-World Study

Illini

Fabikan

Hochmair

et al. 2022

JCM

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About 15% of patients with non-small cell lung cancer (NSCLC) harbor the Kirsten rat sarcoma homolog G12C mutation (KRASG12C). Selective KRASG12C inhibitors offer new treatment opportunities, but little is known about the prevalence, characteristics, and outcomes of standard-of-care treatment (SOC) in this population. We retrospectively assessed the clinicopathological features of patients with KRASG12C-mutated advanced NSCLC and responses to SOC at two high-volume centers in Austria. Out of 2495 NSCLC patients tested, we identified 174 patients with advanced-stage disease carrying a KRASG12C mutation. Most patients were ≥65 years old (55%), heavy smokers (55%), and presented with comorbidities. The most frequent co-alteration was TP53 (18%). PD-L1 expression was high (TPS ≥ 50%) in 31%, very high (TPS ≥ 90%) in 11%, and negative in 31% of patients. A total of 138 patients (79%) received oncologic systemic treatment. The most common first-line therapy (1 L) was anti-PD-1/PD-L1 plus platinum-based chemotherapy. Median overall survival measured from 1 L treatment was 15.3 months (95% CI, 8.6–21.9), 9.4 (95% CI, 5.3–13.5) from 2 L treatment, and 8.4 (95% CI, 1.7–15.1) from 3 L treatment. The time-to-next-treatment was 8.4 (95% CI, 5.2–11.6) from 1 L and 6.1 (95% CI, 2.7–9.7) months from 2 L to 3 L. These poor outcomes underscore the need for the implementation of new treatment options and for specific molecular testing.

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“…Clinical trials for NSCLC patients with KRAS non-G12C mutations have previously been reviewed [ 37 ]. The long-term efficacy of the current KRAS G12C inhibitors remains unclear, mostly due to toxicity and acquired resistance mechanisms [ 26 , 29 , 38 , 39 ].…”

Section: Strategies To Target Oncogenic Mutant Krasmentioning

confidence: 99%

Synthetic Vulnerabilities in the KRAS Pathway

Román

Hwang

Sweet-Cordero

2022

Cancers

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Mutations in Kristen Rat Sarcoma viral oncogene (KRAS) are among the most frequent gain-of-function genetic alterations in human cancer. Most KRAS-driven cancers depend on its sustained expression and signaling. Despite spectacular recent success in the development of inhibitors targeting specific KRAS alleles, the discovery and utilization of effective directed therapies for KRAS-mutant cancers remains a major unmet need. One potential approach is the identification of KRAS-specific synthetic lethal vulnerabilities. For example, while KRAS-driven oncogenesis requires the activation of a number of signaling pathways, it also triggers stress response pathways in cancer cells that could potentially be targeted for therapeutic benefit. This review will discuss how the latest advances in functional genomics and the development of more refined models have demonstrated the existence of molecular pathways that can be exploited to uncover synthetic lethal interactions with a promising future as potential clinical treatments in KRAS-mutant cancers.

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Targeting KRAS in NSCLC: Old Failures and New Options for “Non-G12c” Patients

Cited by 14 publications

References 108 publications

NKp44-Derived Peptide Used in Combination Stimulates Antineoplastic Efficacy of Targeted Therapeutic Drugs

NKp44-Derived Peptide Used in Combination Stimulates Antineoplastic Efficacy of Targeted Therapeutic Drugs

Characteristics and Treatment Outcomes in Advanced-Stage Non-Small Cell Lung Cancer Patients with a KRAS G12C Mutation: A Real-World Study

Synthetic Vulnerabilities in the KRAS Pathway

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