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

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6332
Author(s):  
Francesca Jacobs ◽  
Massimiliano Cani ◽  
Umberto Malapelle ◽  
Silvia Novello ◽  
Valerio Maria Napoli ◽  
...  
Keyword(s):  
Treatment Options ◽  
Gene Mutations ◽  
Kras Gene ◽  
Kras Mutations ◽  
Exon 2 ◽  
Intrinsic Complexity ◽  
Nsclc Patients ◽  
Critical Overview ◽  
Kras Exon ◽  
Viral Oncogene Homolog

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene mutations are among the most common driver alterations in non-small cell lung cancer (NSCLC). Despite their high frequency, valid treatment options are still lacking, mainly due to an intrinsic complexity of both the protein structure and the downstream pathway. The increasing knowledge about different mutation subtypes and co-mutations has paved the way to several promising therapeutic strategies. Despite the best results so far having been obtained in patients harbouring KRAS exon 2 p.G12C mutation, even the treatment landscape of non-p.G12C KRAS mutation positive patients is predicted to change soon. This review provides a comprehensive and critical overview of ongoing studies into NSCLC patients with KRAS mutations other than p.G12C and discusses future scenarios that will hopefully change the story of this disease.

scholarly journals KRAS and NRAS mutational gene profile of metastatic colorectal cancer patients in Jordan: Molecular spectrum, frequency and distribution pattern

2019 ◽  
Author(s):  
Muhammad Awidi ◽  
Nidaa Ababneh ◽  
Maha Shomaf ◽  
Feras Al Fararjeh ◽  
Laila Owaidi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Distribution Pattern ◽  
Cancer Patients ◽  
Molecular Spectrum ◽  
Kras Mutations ◽  
Exon 2 ◽  
Ras Mutations ◽  
Colorectal Cancer Patients ◽  
Kras Exon

Abstract Background A constitutively active RAS protein in the absence of stimulation of the epidermal growth factor receptor (EGFR) is the result of mutations in KRAS and NRAS genes. Mutations in the KRAS exon 2 and outside exon 2 have been found to predict the resistance to anti-EGFR monoclonal therapy. A substantial proportion of metastatic colorectal cancer cases (mCRC) exhibit RAS mutations outside KRAS exon 2, particularly in KRAS exon 3 and 4 and NRAS exons 2, 3. No data about RAS mutations outside KRAS exon 2 are available for Jordanian patients with mCRC. We aim to study the molecular spectrum, frequency, and distribution pattern of KRAS and NRAS mutations in Jordanian patients with mCRC. Methods A cohort of 190 Jordanian metastatic colorectal cancer patients were enrolled in the trial. We detected mutations in exon 2 of the KRAS and NRAS gene as well as mutations outside of exon 2 using the StripAssay technique. The KRAS StripAssay covered 29 mutations and 22 NRAS mutations. Results Mutations were observed in 92 (48.42%) cases, and KRAS exon 2 accounted for 76 cases (83.69%). KRAS G12D was the most common mutation, occurring in 18 cases, followed by KRAS G12A in 16 cases, and G12T in 13 cases. Mutations outside of KRAS exon 2 represented 16.3% of the mutated cases. Among those, 6 cases (6.48%) carried mutations in NRAS exon 2, 3 and 10 cases (10.87%) in KRAS exon 3 and 4. Conclusion The frequency of NRAS and KRAS mutations outside of exon 2 appears to be higher in Jordanian patients in comparison with patients from western countries. KRAS mutations outside of exon 2 should be tested routinely to identify patients who should not be treated with anti-EGFR antibodies.

scholarly journals Current Approaches in NSCLC Targeting K-RAS and EGFR

2019 ◽  
Vol 20 (22) ◽  
pp. 5701 ◽  
Author(s):  
Veronica Aran ◽  
Jasminka Omerovic
Keyword(s):  
Treatment Options ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Response To Therapy ◽  
Small Cell Lung ◽  
Ras Mutations ◽  
Tk Inhibitors ◽  
Epidermal Growth ◽  
Nsclc Patients ◽  
Viral Oncogene Homolog

The research and treatment of non-small cell lung cancer (NSCLC) have achieved some important advances in recent years. Nonetheless, the overall survival rates for NSCLC remain low, indicating the importance to effectively develop new therapies and improve current approaches. The understanding of the function of different biomarkers involved in NSCLC progression, survival and response to therapy are important for the development of early detection tools and treatment options. Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (K-RAS) are two of the main significant biomarkers for the management of NSCLC. Mutations in these genes were associated with development and response to therapies. For example, the use of small molecule tyrosine kinase (TK) inhibitors and immunotherapy has led to benefits in some, but not all patients with altered EGFR. In contrast, there is still no effective approved drug to act upon patients harbouring K-RAS mutations. In addition, K-RAS mutations have been associated with lack of activity of TK inhibitors. However, promising approaches aimed to inhibit mutant K-RAS are currently under study. Therefore, this review will discuss these approaches and also EGFR therapies, and hopefully, it will draw attention to the need of continued research in the field in order to improve the outcomes in NSCLC patients.

Molecular analysis of NSCLC patients with acquired resistance to gefitinib or erlotinib

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7078-7078 ◽  
Author(s):  
W. Pao ◽  
M. N. Balak ◽  
G. J. Riely ◽  
A. R. Li ◽  
M. F. Zakowski ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Kinase Domain ◽  
Site Mutation ◽  
Primary Resistance ◽  
Kras Mutations ◽  
T790m Mutation ◽  
Exon 2 ◽  
Nsclc Patients ◽  
Egfr Kinase ◽  
Exon 19

7078 Background: We previously reported that in 2 of 5 non-small cell lung cancer (NSCLC) patients with acquired resistance to the tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, tumors biopsied after disease progression contained a second site mutation (T790M) in the epidermal growth factor receptor (EGFR) kinase domain, in addition to a primary drug-sensitive mutation (exon 19 deletion (del) or exon 21 point mutation (L858R)) (Pao et al, PLoS Med ‘05). No patients had KRAS mutations, which are associated with primary resistance to these TKIs. We sought to determine the frequency of second site EGFR kinase domain and KRAS mutations in tumors from patients with acquired resistance to TKIs, administered either as monotherapy or with chemotherapy. Methods: 18 patients with NSCLC who responded to either TKI alone (n = 14) or TKI plus chemotherapy (n = 4) and then progressed were re-biopsied. Genomic DNA samples from tumors were examined for EGFR (exons 18–24) and KRAS (exon 2) mutations. Results: Sequence analysis was successfully performed on tumors from 17 patients. The T790M EGFR mutation was detected in 6 of 13 (46%, 95% CI 19–75%) on TKI monotherapy, and in 0 of 4 (0%, 95% CI 0–53%) on TKI plus chemotherapy. In one autopsy case, the T790M mutation was detected in 5 of 5 sites, which all harbored the same exon 19 del. No other EGFR or KRAS mutations were detected. Conclusions: Secondary EGFR T790M but not KRAS mutations are commonly associated with acquired resistance to TKI monotherapy. More patients are being studied, and we are trying to elucidate determinants of acquired resistance in the absence of T790M mutations. New therapies are needed to treat and/or suppress the development of acquired resistance to gefitinib or erlotinib. Support: Joan’s Legacy, DDCF, K08-CA097980, R21-CA115051. [Table: see text]

Prognostic value of KRAS exon 2 gene mutations in stage III colon cancer: Post hoc analyses of the PETACC8 trial.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 3549-3549
Author(s):  
Julien Taïeb ◽  
Jean-François Emile ◽  
Karine Le Malicot ◽  
Aziz Zaanan ◽  
Josep Tabernero ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Prognostic Value ◽  
Gene Mutations ◽  
Stage Iii ◽  
Exon 2 ◽  
Stage Iii Colon Cancer ◽  
Post Hoc ◽  
Kras Exon

scholarly journals Necessity of Microdissecting Different Tumor Components in Pulmonary Tumor Pyrosequencing

2016 ◽  
Vol 2016 ◽  
pp. 1-5
Author(s):  
Dahui Qin ◽  
Zhong Zheng ◽  
Shanxiang Shen ◽  
Prudence Smith ◽  
Farah K. Khalil
Keyword(s):  
Gene Mutations ◽  
Molecular Testing ◽  
Tissue Sampling ◽  
Wild Type ◽  
Kras Mutations ◽  
Viral Oncogene ◽  
Pulmonary Tumor ◽  
New Challenges ◽  
Murine Sarcoma ◽  
Viral Oncogene Homolog

Microdissection is a useful method in tissue sampling prior to molecular testing. Tumor heterogeneity imposes new challenges for tissue sampling. Different microdissecting methods have been employed in face of such challenge. We improved our microdissection method by separately microdissecting the morphologically different tumor components. This improvement helped the pyrosequencing data analysis of two specimens. One specimen consisted of both adenocarcinoma and neuroendocrine components. When both tumor components were sequenced together for KRAS (Kirsten rat sarcoma viral oncogene homolog) gene mutations, the resulting pyrogram indicated that it was not a wild type, suggesting that it contained KRAS mutation. However, the pyrogram did not match any KRAS mutations and a conclusion could not be reached. After microdissecting and testing the adenocarcinoma and neuroendocrine components separately, it was found that the adenocarcinoma was positive for KRAS G12C mutation and the neuroendocrine component was positive for KRAS G12D mutation. The second specimen consisted of two morphologically different tumor nodules. When microdissected and sequenced separately, one nodule was positive for BRAF (v-raf murine sarcoma viral oncogene homolog B1) V600E and the other nodule was wild type at the BRAF codon 600. These examples demonstrate that it is necessary to microdissect morphologically different tumor components for pyrosequencing.

scholarly journals Prognostic and Predictive Value of RAS Gene Mutations in Colorectal Cancer: Moving Beyond KRAS Exon 2

Drugs ◽  
2015 ◽  
Vol 75 (15) ◽  
pp. 1739-1756 ◽  
Author(s):  
Nele Boeckx ◽  
Marc Peeters ◽  
Guy Van Camp ◽  
Patrick Pauwels ◽  
Ken Op de Beeck ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Predictive Value ◽  
Gene Mutations ◽  
Ras Gene ◽  
Exon 2 ◽  
Kras Exon

scholarly journals KRAS gene mutation in patients with primary colorectal cancer

Acta Medica ◽  
2019 ◽  
Vol 50 (1) ◽  
pp. 20-25
Author(s):  
Minh Thuc Vu Thi ◽  
Van Thieu Le ◽  
Quang Huy Huynh ◽  
Minh Duc Nguyen
Keyword(s):  
Colorectal Cancer ◽  
Gene Mutation ◽  
Kras Mutation ◽  
Pcr Amplification ◽  
Colorectal Cancers ◽  
Kras Gene ◽  
Kras Mutations ◽  
Exon 2 ◽  
Mutational Status ◽  
Keywords Colorectal Cancer

Objective: KRAS mutation occurs in 30% to 50% of colorectal cancers. The aim of our study was to determine the frequency of KRAS mutations among patients with colorectal cancer; and the relationship with clinicopathologic features. Materials and Methods: 79 colorectal cancer cases at a hospital in Hai Phong of Vietnam were collected, including 45 colon cancer and 34 rectal cancer during January 2010 and July 2012. PCR amplification and DNA sequencing were used to detect mutations in exon 2 of KRAS gene. The study was based on informed consent and approval by the Ethics Committee of Viet Tiep Hospital. Results: KRAS mutation was found in 40.4% (225/557) colorectal cancer. All mutation locations were in codon 12. There was significant association (p < 0.05) between KRAS mutations, tumor size and tumor stage. No significant association was observed between KRAS mutations and gender, tumor location, tumor grade or histologic presence of mucin (p>0.05). Conclusion: Determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers Keywords: colorectal cancer, KRAS gene mutation, clinicopathology.

Clinical characteristics, co-mutations and outcomes of advanced non-small cell lung cancer (NSCLC) patients with KRAS mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21174-e21174
Author(s):  
Arun Muthiah ◽  
Rani Chudasama ◽  
Adam J. Olszewski ◽  
Harish Saiganesh ◽  
Habibe Kurt ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Initial Therapy ◽  
New Drugs ◽  
Molecular Characteristics ◽  
Data Sets ◽  
Kras Gene ◽  
Kras Mutations ◽  
Nsclc Patients ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

e21174 Background: Mutations (mt) in the KRAS gene are common oncogenic drivers in advanced NSCLC. The KRAS mt subtypes and certain co-mutations (co-mt) have prognostic and predictive implications. New drugs promise to uniquely target KRAS G12C, raising interest in studying the unique clinical and molecular characteristics of this subtype. Methods: We retrospectively identified 56 KRAS mt advanced NSCLC patients (pts) that underwent Next-Generation Sequencing (NGS) from 06/2015 to 12/2020. We used a commercial NGS panel that tested for > 300 genomic alterations, including substitutions, insertions, deletions and copy number alterations. For statistical analysis, we divided the patients into G12C and non-G12C groups. Results: In our cohort of 56 KRAS mt pts, median age was 67 (range: 58-74) with a predominance of females (63%) and heavy smokers (89%). KRAS G12C was the most common subtype 38%; G12V 14%, G12D 11%, G12S 11%, G13D 7% and others < 5% each. G12C, G12D and G13D groups had a higher proportion of PD-L1+ tumors (84%, 100%, and 100% respectively, p = 0.02) compared to other KRAS subtypes. Pts in G12C group were on average older (median age 71 vs 61, p = 0.02) than non-G12C. Most frequent co-mt in G12C were TP53 (33%), STK11 (29%), TET2 (19%), RB1 (14%), CDKN2A/B (14%) , MCL1 (14%) and ASXL1 (14%) ; for non-G12C, they were TP53 (54%), CDKN2A/B (37%), STK11 (34%) and RBM10 (17%). CDKN2A/B co-mt (37% vs 14%, p = 0.08) was significantly more frequent in non-G12C group and TET2 in G12C (19% vs 0%, p = 0.016). Non-G12C group more frequently had high TMB (17% vs 0%, p = 0.07) compared to G12C. No difference in survival was seen between G12C and non-G12C groups. We observed no difference in PFS (p = 0.31) or OS (p = 0.64) between smokers and no/light-smokers with KRAS mt. Co-mt with KEAP1 and SMARCA4 were significantly associated with survival in KRAS mt. Compared to KRAS+/KEAP1wt, KRAS +/ KEAP1+ pts had poor PFS (median 1.1 vs 7.5 m, p < 0.0001) and OS (1.1 vs. 27.8 m, p < 0.0001) measured from start of initial therapy. KRAS+/SMARCA4+ had worse PFS (1.0 vs 6.9 m, p < 0.0001) and OS (1.4 vs. 27.8, p = 0.0001) compared to KRAS+/SMARCA4wt. KRAS mt pts with STK11/KEAP1 that were treated with immunotherapy-based regimens had shorter PFS (1.1 vs 7.6 m, p = 0.001) and OS (1.4 vs 90.9 m, p = 0.0007) compared to those treated with chemotherapy alone. Conclusions: Our data shows that pts with KRAS co-mt with STK11/KEAP1 had worse PFS and OS with the addition of immunotherapy compared to chemotherapy alone, highlighting the potential implications of these co-mt patterns on treatment outcomes. The types of co-mts are similar between KRAS G12C and non-G12C, with the exception of CDKN2A/B (less likely) and TET2 (more likely). Larger data sets are warranted to confirm our observations and determine if these co-mts may create a predictive model for individualized therapy for KRAS mt pts, potentially independent of current predictive markers.

scholarly journals The value of haematological parameters and serum tumour markers for predicting KRAS mutations in 784 Chinese colorectal cancer patients: a retrospective analysis

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yinghao Cao ◽  
Junnan Gu ◽  
Lizhao Yan ◽  
Shenghe Deng ◽  
Fuwei Mao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Logistic Regression ◽  
Predictive Value ◽  
Gene Mutations ◽  
Haematological Parameters ◽  
Multivariate Logistic Regression ◽  
Kras Gene ◽  
Kras Mutations ◽  
Mutation Status ◽  
Serum Tumour

Abstract Background Identifying the mutation status of KRAS is important for optimizing treatment in patients with colorectal cancer (CRC). The aim of this study was to investigate the predictive value of haematological parameters and serum tumour markers (STMs) for KRAS gene mutations. Methods The clinical data of patients with colorectal cancer from January 2014 to December 2018 were retrospectively collected, and the associations between KRAS mutations and other indicators were analysed. Receiver operating characteristic (ROC) curve analysis was performed to quantify the predictive value of these factors. Univariate and multivariate logistic regression models were applied to identify predictors of KRAS mutations by calculating the odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). Results KRAS mutations were identified in 276 patients (35.2%). ROC analysis revealed that age, CA12–5, AFP, SCC, CA72–4, CA15–3, FERR, CYFRA21-1, MCHC, and tumor location could not predict KRAS mutations (P = 0.154, 0.177, 0.277, 0.350, 0.864, 0.941, 0.066, 0.279, 0.293, and 0.053 respectively), although CEA, CA19–9, NSE and haematological parameter values showed significant predictive value (P = 0.001, < 0.001, 0.043 and P = 0.003, < 0.001, 0.001, 0.031, 0.030, 0.016, 0.015, 0.019, and 0.006, respectively) but without large areas under the curve. Multivariate logistic regression analysis showed that CA19–9 was significantly associated with KRAS mutations and was the only independent predictor of KRAS positivity (P = 0.016). Conclusions Haematological parameters and STMs were related to KRAS mutation status, and CA19–9 was an independent predictive factor for KRAS gene mutations. The combination of these clinical factors can improve the ability to identify KRAS mutations in CRC patients.

High-sensitivity KRAS mutation detection in colorectal and lung cancer using SURVEYOR Nuclease scanning

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22023-e22023
Author(s):  
M. Koul ◽  
S. Mahurkar ◽  
B. Legendre ◽  
J. Jiang ◽  
E. Kaldjian
Keyword(s):  
Lung Cancer ◽  
Mutation Detection ◽  
Growth Factor Receptor ◽  
Splice Junction ◽  
Coding Region ◽  
Kras Gene ◽  
Kras Mutations ◽  
Exon 2 ◽  
Base Pair Mismatch ◽  
Surveyor Nuclease

e22023 Background: Mutations of the KRAS gene in colorectal and lung cancers have been associated with lack of response to epidermal growth factor receptor (EGFR) inhibitor therapies. Here we describe a highly sensitive assay that identifies mutations by scanning the entire coding region of KRAS exons 2 and 3 using SURVEYOR Nuclease, an endonuclease that cleaves double-stranded heteroduplex DNA at base pair mismatch sites. Methods: DNA was extracted from formalin-fixed paraffin- embedded tissue sections from a set of 30 colorectal and lung cancer samples. Two amplicons covering the coding and splice junction regions of the KRAS gene exons 2 and 3 were PCR-amplified, hybridized to allow heteroduplex formation, incubated with SURVEYOR Nuclease and analyzed on the WAVE-HS DHPLC system. The sensitivity of SURVEYOR Nuclease mutation detection was assessed by creating serial dilutions of 50:50 mixtures of original PCR products from mutant samples with wild type amplicons from control DNA. Results: 6 samples were identified as KRAS mutant by WAVE-HS profiles containing two fragment peaks in addition to the full length amplicon peak, indicating SURVEYOR Nuclease cleavage at a mismatch site. Mutations were found in both exon 2 (codons 12, 13) and exon 3 (codon 59). Sequencing confirmed the KRAS mutations in these samples. Levels of mutant DNA as low as 2% (1 ng/ul) were identified by this method, consistent with other SURVEYOR-based assays. Conclusions: SURVEYOR Nuclease technology is a sensitive and comprehensive method for detecting mutation in KRAS. [Table: see text]

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