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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 516-523

Biomarker series: KRAS- A narrative review

1 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
2 Department of Section of Molecular Diagnostics, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India

Date of Submission12-Aug-2021
Date of Decision05-Sep-2021
Date of Acceptance16-Sep-2021
Date of Web Publication08-Oct-2021

Correspondence Address:
Ullas Batra
Sector 5, Rohini, Sir Chhotu Ram Marg, New Delhi - 110 085
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_189_21

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Non-small cell lung cancer (NSCLC) has emerged as the poster child of molecular medicine. Kirsten rat sarcoma (KRAS)-mutated NSCLC is a common yet heterogeneous entity with distinct clinical and prognostic characteristics. Therapeutically, targeting the KRAS mutation in NSCLC has been the most difficult challenge faced by scientists and drug developers and after decades of efforts, a final breakthrough in the form of KRAS G12C inhibitors has emerged. In this edition of the biomarker series, we review KRAS, its biology, clinical features, and the therapeutic options in KRAS-mutant NSCLC. We performed a thorough search in PubMed, Embase, and Scopus and finally included 59 articles to write this review.

Keywords: G12C, Kirsten rat sarcoma, sotorasib, KRAS

How to cite this article:
Batra U, Nathany S. Biomarker series: KRAS- A narrative review. Cancer Res Stat Treat 2021;4:516-23

How to cite this URL:
Batra U, Nathany S. Biomarker series: KRAS- A narrative review. Cancer Res Stat Treat [serial online] 2021 [cited 2022 May 16];4:516-23. Available from: https://www.crstonline.com/text.asp?2021/4/3/516/327779

  Introduction Top

The last decade has seen a paradigm shift in the development of molecular targeted therapies which have ushered in a new era of precision and personalized medicine. Oncogenic mutations in genes such as FLT3, and IDH, and oncogenic fusions have been among the first targets to be discovered. Tumor suppressors still remain outside the purview of targeted therapy except BRCA genes. The rat sarcoma virus (RAS) family of genes has been commonly implicated in malignancies of the colon, lung, and pancreas, with Kirsten RAS (KRAS) viral oncogene homolog being the most frequent oncogenic mutation detected in non-small-cell lung carcinoma (NSCLC).[1] KRAS accounts for almost 30% of cases of lung adenocarcinomas in the West and close to 10% in Asia,[2] with KRAS G12C (glycine to cysteine substitution at codon 12 of KRAS) mutation being the most common.[3],[4] Recent developments in the understanding of biological heterogeneity and disease pathobiology have led to unprecedented hopes for precision medicine in this group of patients. Until very recently considered “undruggable” despite numerous efforts, KRAS has finally emerged as a molecular target with new drugs approved in this space, and many in the pipeline.

The aim of this review article is to describe the structure, and molecular biology of KRAS, and the clinical characteristics, along with the most recent advances in the therapeutic strategies in KRAS-mutant NSCLC.

  Methods Top

This is a narrative review; we did not perform a meta-analysis or systematic analysis. Therefore, we did not apply specific inclusion/exclusion criteria to select articles for this review. The articles were identified by searching PubMed, EMBASE, Scopus, and My Cancer Genome, using the keywords “G12C,” “KRAS,” “NSCLC,” and “Sotorasib.” A total of 59 articles were finally included for preparing the review

  Historical Perspective Top

The oncogenic ability of KRAS was discovered almost four decades ago, by Scolnick et al.and Scolnick and Parks[5],[6] in their study on the nucleic acid structure of KRAS. The relationship of RAS and lung cancer was established later in 1984 by Malumbres and Barbacid[7] in a landmark study demonstrating the presence of KRAS mutation in a specimen of lung, which was absent in normal lung tissue.

  Molecular Biology Top


KRAS maps to the short arm of chromosome 12 (chr12p12.1).[7] KRAS is a member of the RAS family of proteins which also includes Harvey RAS viral oncogene homolog and neuroblastoma RAS viral oncogene homolog. These proteins belong to the family of small guanosine triphosphatases and are intracellular guanine nucleotide-binding proteins. The structure comprises a catalytic domain (G domain) which is responsible for binding of guanine and activation of signaling, and a hypervariable C-terminal region which houses farnesyl or prenyl groups which are post-transcriptional modifications, and diverge in various isoforms to help in localization of the RAS proteins to the cell membranes.[8]


The downstream signaling involves two alternative states of the RAS proteins, i.e., RAS-GTP which is the active form and RAS-GDP which is the inactive form. The active complex is involved in activation of several downstream pathway effectors such as Raf-MEK-ERK, PI3K-AKT-mTOR, and the RalGDS-RalA/B pathways. These pathways control multiple functions in the cell including cellular proliferation, apoptosis, cell motility, and survival. Constitutive activation of KRAS occurs by the binding of several growth factors to their receptors, including epidermal growth factor receptor (EGFR) which is the most relevant in lung cancer. Adaptor proteins act together with the intracellular domain of EGFR and recruit factors such as Son of Sevenless (SOS) where they combine with RAS to facilitate the exchange of GDP for GTP. RAS has an intrinsic GTPase activity by interaction with GTPase activating proteins and it causes hydrolysis of GTP to GDP, terminating the RAS signaling. Mutations in RAS molecules impair this intrinsic GTPase activity, thus locking it in an active GTP conformation, independent of the upstream signal.[7] A schematic representation of the KRAS signaling is depicted in [Figure 1].
Figure 1. Signaling of KRAS. GDP: Guanosine diphosphate, GTP: Guanosine triphosphate, TIAM1: Tumor invasion and metastasis inducing protein 1, RAC:Rho-like GTPase.

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Mutations and isoforms

KRAS4A and KRAS4B are two highly similar proteins located at the KRAS locus, and are the result of alternative splicing which leads to a structural difference only in their C-termini. 4B is ubiquitous in expression, whereas 4A is tissue-specific and is essential in lung cancer carcinogenesis.

Most mutations in KRAS occur in exons 2 and 3 of the gene.[8] Missense mutations are the most commonly occurring genomic alterations, which can arise either due to transition (G>A) resulting in G12D and G13D mutations, or due to transversions (G>T or G>C) resulting in G12V and G12C mutations. The most frequent among these in NSCLC is the G12C occurring in ~50% of cases.[9] Other mutations involving the Q61 and A146 codons have been rarely reported in NSCLC, however, are canonical in colorectal and pancreatic cancers. [Table 1] depicts the frequencies of different alterations in lung adenocarcinoma and squamous cell carcinoma in the Cancer Genome Atlas and the Memorial Sloan Kettering Cancer Center (MSKCC) cohorts.
Table 1: Mutation specific frequencies in the Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center primary lung adenocarcinoma cohorts and the Cancer Genome Atlas squamous cell carcinoma cohort

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  Clinical Characteristics Top

Clinical features

KRAS mutations in NSCLC are associated with a distinct clinicodemographic patient profile, and are noted more commonly in female patients, smokers, and tumors with mucinous histology.[10] KRAS mutations were detected in 22% cases in a cohort of 500 patients of lung adenocarcinomas from the MSKCC, New York, USA.[11] The transversion mutations as described above have been found to be more common in ever-smokers when compared to the transition mutations which are more common in never-smokers. In the Lung Cancer Mutation Consortium Study[12] on 1655 patients, 27% were found to harbor KRAS mutations, with the majority of patients (53%) being female and smokers (93%). This is in contrast to other commonly implicated biomarkers such as EGFR, ALK, and ROS1 which are more commonly altered in non-smokers. In an Indian study by Chandrani et al.,[13] involving 45 NSCLC patients, KRAS mutations were detected in 13% of cases. In another contemporary Indian study by Tripathi et al.,[14] among the 50 solid tumors that were noted to have KRAS mutation, 25 (50%) cases were of NSCLC. Considering squamous histology separately, 1.1% of cases in an Indian cohort were detected to harbor a KRAS mutation.[15]

Prognostic significance

The presence of a mutation in KRAS has been found in many studies to have a negative impact on prognosis, whereas other researchers have reported no significant association with survival. In a meta-analysis of 53 studies, Mascaux et al.[16] found that the presence of a KRAS mutation correlated with a worse prognosis (hazard ratio [HR] 1.40; P = 0.01). Contrary to this, Villaruz et al.,[17] in a study at Pittsburgh, USA, on 998 patients with lung adenocarcinomas, concluded that KRAS was not an individual prognostic factor. In a landmark study which involved a pooled analysis of four trials investigating the role of adjuvant chemotherapy[18] in 1500 patients of mixed ethnicities with NSCLC, including 300 patients harboring KRAS-mutant tumors, the presence of KRAS mutation was found to be of no prognostic significance. Another study involving 1935 patients of mixed ethnicities with lung cancer[19] found that patients with wild type KRAS had a clear overall survival (OS) advantage, whereas in the meta-analysis involving patients with different ethnic origins by Fan et al.,[20] the presence of KRAS mutation in circulating tumor DNA was associated with a shorter progression-free survival (PFS) and OS. In a study involving 6939 patients[21] that compared the difference in survivals between patients belonging to different ethnic groups, the authors concluded that the HR for PFS in Asians was higher when compared to non-Asians with KRAS-mutant lung cancer, indicating a comparatively worse prognosis in the Asian KRAS-mutant cohort. There are no large-scale studies from the Indian subcontinent regarding the prognostic implications of KRAS mutations in lung cancer.

Heterogeneity exists within the different mutation subgroups of KRAS-mutated NSCLC. The G12V mutation has been reported to be associated with better response rates to chemotherapy and slightly longer PFS. This finding was corroborated by pre-clinical studies done by Garassino et al.,[22] who found that G12V-mutant tumor cells were more sensitive to cisplatin. They also demonstrated that the G12D mutation led to an increased resistance to paclitaxel but increased sensitivity to sorafenib. They also demonstrated that the presence of the G12C mutation was associated with a reduced response to cisplatin and increased sensitivity to paclitaxel and pemetrexed.

  Co-Occurring Genomic Alterations in Alterations in KRAS-Mutated NSCLC Top

An important aspect of KRAS-mutant NSCLC is the presence of heterogeneity not only in the KRAS genomic loci but also due to frequently co-occurring genomic alterations. These include alterations in genes such as TP53 (39.4%), CDKN2A/2B, STK11 (19.8%), and KEAP1 (12.9%).[10] These have been reported to have important implications on disease behavior as well as therapeutic vulnerabilities. Tumors with co-mutated STK11/KEAP1[23] show reduced responses to immune checkpoint inhibition when compared to the other two types (KRAS with TP53 shows good response, whereas KRAS with coexistent CDKN2A/2B shows an intermediate response to immunotherapy) described. There are also differences in the relapse-free survival when comparing the tumors that have TP53 with KRAS co-mutations and the others (KRAS with STK11/LKB1 and KRAS with CDKN2A/2B subgroups), with the former showing longer relapse-free survival when compared to the other two subgroups (KRAS with STK11/LKB1 and KRAS with CDKN2A/2B subgroups). Skoulidis et al.[24] conducted an integrative study involving genomics, transcriptomics, and proteomics in KRAS-mutant NSCLC and found three distinct subsets defined by the presence of co-occurring alterations. These are depicted in [Table 2]. Other co-occurring alterations include MET amplification (15.4%), ERBB2 amplification (13.8%), EGFR (1.2%), and BRAF (1.2%). The interesting relationship between coexistent EGFR mutation with KRAS mutation has been studied widely. In a study by Noronha et al. and Choughule et al.,[25],[26] KRAS sequencing was performed in 86 NSCLC patients; 18.6% had a coexistent KRAS mutation (15 were found to have a coexistent KRAS G12C and 1 patient harbored a G12V mutation). Three of the G12C mutant tumors harbored a deletion in exon 19 in EGFR and attained a partial response to EGFR TKI therapy. However, 12 of 13 patients who harbored a G12C mutation with wild-type EGFR, did not show a response to EGFR TKI. This implies that the presence of a KRAS mutation with EGFR wild-type status is not predictive of response to EGFR TKI therapy, and hence, selecting patients for EGFR TKI does not warrant KRAS testing in NSCLC. The same results have been corroborated in studies in the rest of the world.[27],[28]
Table 2: Comparison of subgroups based on co-occurring alterations

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  Detection of KRAS Alterations Top

Missense mutations are the most common alterations in most oncogenes; hence, KRAS alterations have been traditionally detected using simple polymerase chain reaction (PCR)-based techniques involving the allele-specific PCR, and real-time PCR. Direct sequencing using the Sanger technique and nowadays next-generation sequencing (NGS)-based panels are also being widely employed. Incorporation of KRAS testing in the new National Comprehensive Cancer Network guidelines for biomarker testing in second-line testing (after testing for EGFR, ALK, ROS1) for NSCLC, especially in smokers, has led to the emergence of liquid biopsy-based detection methods including Droplet Digital PCR as well as the Roche Cobas V2 platform. However, since the adequacy of tissue in cases of NSCLC is a major concern in modern-day molecular biology, KRAS has been incorporated into targeted as well as larger gene panels for use in NGS-based panels. These not only offer a higher throughput but also help determine the co-mutation profile which may have important therapeutic implications. A detailed description and comparison of various techniques used to detect KRAS mutation is depicted in [Table 3].[29],[30],[31],[32]
Table 3: Comparison of various detection methods for KRAS mutation

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  Therapeutic Options Top

High affinity of RAS for GTP/GDP and high intracellular concentrations have been the main reasons for failure of in-vivo blockage of the catalytic site using competitive inhibitors. Hence, efforts in the past have mainly relied on indirect targeting of KRAS either using conventional cytotoxic chemotherapy or inhibition of other downstream effectors, as described earlier.[10],[33],[34]

  Past efforts and results Top

Results from the Phase III SELECT-1 trial showed that adding the MEK inhibitor, selumetinib, to docetaxel did not prolong the PFS when compared to chemotherapy alone in KRAS-mutant NSCLC; the reported median PFS was 3.9 months for the combination versus 2.8 months for docetaxel alone, (P = 0.44).[35] Trametinib, another MEK1/2 inhibitor, did not result in an improved PFS or response rate when compared with docetaxel.[36] The BASALT-1 study[37] investigating the pan-PI3K inhibitor, buparlisib, was also stalled early due to disappointing interim results.

Two classes of cysteine 12 modifying inhibitors have been developed recently which bind to the KRAS nucleotide pocket. KRAS G12C is found in 3% of colorectal cancers, 13% of cases of all lung cancers, and in 50% of all KRAS-mutant NSCLC.[34] In tumors that harbor the KRAS G12C mutation, the cysteine is located in a cryptic pocket in the GDP-KRAS, for which covalent inhibitors targeting this cryptic pocket have been developed, which, in turn, lead to allosteric inhibition of the 12-cysteine codon.[38]

Direct KRAS G12C inhibitors


Sotorasib (AMG 510)[39] is an orally active KRAS G12C inhibitor which permanently blocks the KRAS G12C in an inactive GDP-complex state. In the CodeBreaK100 trial,[40] which investigated the efficacy of sotorasib in pre-treated solid tumors including colorectal and NSCLC, a disease control rate of 88.1% was achieved in patients with NSCLC and 73.8% in patients with colorectal cancer. The median PFS attained was 6.3 months in the patients with NSCLC, and 4 months for the patients with colorectal malignancies. It was also found to be safe with an acceptable toxicity profile; the common adverse events were diarrhea, fatigue, and nausea. Hong et al.,[39] in a phase I study of sotorasib in 129 patients with KRAS G12C-mutant NSCLC, demonstrated an objective response rate of 32% and a disease control rate of 88%. The median time to response was 1.4 months and the median duration of response was 10.9 months.

The results of the Phase II CodeBreaK100 study[41] in 126 patients with advanced NSCLC who were KRAS G12C mutant were reported at the World Conference on Lung Cancer 2020. Of the total cohort of patients, 46 demonstrated a confirmed response resulting in an objective response rate of 37% and a disease control rate of 80%. The safety profile was excellent with no treatment-related deaths, and the most frequent Grade 3 adverse events noted were elevation of aminotransferases (11.9%) and diarrhea (4%).[41] The Phase III CodeBreaK 200 trial (NCT04303780)[42] which is comparing sotorasib with docetaxel in patients who have progressed on platinum-based chemotherapy and immune-checkpoint inhibitors is underway. In view of the promising results, on May 28, 2021, the United States Food and Drug Administration (US FDA) granted accelerated approval to sotorasib for use in patients with locally advanced and metastatic NSCLC with KRAS G12C mutation who have received at least one prior line of cancer-directed therapy. The FDA also approved two companion diagnostic tests - the Qiagen therascreen KRAS RGQ PCR kit and Guardant360 CDx for the detection of KRAS G12C in tissue and blood samples of patients, respectively. The recommended dose of sotorasib as per the FDA label is 960 mg once daily orally, with or without food. Sotorasib demonstrates a time-dependent kinetics, and the median time to reach peak plasma concentration is 1 hour. Consumption of fatty high-calorie foods has been shown to increase absorption by 25%. The metabolism is by non-enzymatic conjugation and through the cytochrome system, and the main route of excretion is in the feces (74%) and partly by renal excretion (6%).[43]


This is another covalent G12C inhibitor developed by Mirati Therapeutics Inc. which binds to the cryptic pocket in GDP-KRAS, inhibiting the KRAS pathway.[44] There were 110 patients of NSCLC, colorectal, pancreatic, ovarian, and endometrial tumors with KRAS G12C mutation enrolled in the KRYSTAL-1 study[45] which investigated the efficacy and safety of adagrasib. The preliminary results were presented at the 32nd EORTC-NCI-AACR Symposium in 2020, in which among the 51 evaluable patients,[45] the objective response rate was reported to be 45% and the disease control rate was 96%. It demonstrated a manageable safety profile with the most common Grade 3 events being diarrhea, nausea, vomiting, fatigue, and elevation of aminotransferases. The clinical trials on direct KRAS inhibitors are summarized in [Table 4]
Table 4: Clinical trials related to direct KRAS G12C inhibitors

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Novel therapeutic approaches under investigation for KRAS-mutated tumors

Despite the success of the direct G12C inhibitors, many other novel therapeutic compounds targeting KRAS are under investigation. This is attributed to the fact that G12C mutation occurs in lower frequency in other malignancies, and numerous acquired resistance mechanisms to G12C inhibition have already been described which activate alternate RAS-dependent mechanisms. An overview of these approaches with the mechanisms of action is provided in [Table 5].
Table 5: Novel therapeutic compounds and their mechanism of action which are under investigation for KRAS inhibition

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Synthetic lethality

Synthetic lethal partners are genes which, if mutated alone, are compatible with viability; pharmacological inhibition of these causes cell death. Many potential synthetic lethal partners have been identified for KRAS which include BCL-XL,[46] FGFR1, CDK4,[47] AKT, XPO1, YAP1, WT1, and GATA2.[48] Trials are evaluating novel mechanisms to inhibit these.

Autophagy inhibition

Autophagy is a cellular process resulting in degradation of the intracellular components. This process is stimulated by the unfolded protein response pathway, nutrient, and oxidative stress. The role of KRAS in this regard has been studied, and the use of hydroxychloroquine which causes inhibition of this process unfortunately failed to show therapeutic activity in patients of pancreatic cancer.[49]

  Resistance Mechanisms to KRAS Inhibition Top

Resistance mechanisms to KRAS G12C inhibition have been described. These include increased receptor tyrosine kinase activity which, in turn, promotes the cycling of G12C to its active form. Inactivity of other growth factor signals can also bypass the blockade leading to intrinsic G12C resistance.[50] High basal EGFR activity,[51] especially in colon cancers, leads to higher phosphorylated ERK and thus KRAS G12C resistance. Other mechanisms include reactivation of the MAPK pathway, PI3K-AKT activation, and activation of receptor tyrosine kinase signalling.[52] Feedback reactivation of wild-type KRAS has also been demonstrated in G12C models.[53] Additional alterations in KRAS including amplification also lead to G12C resistance. Aurora kinase A also promotes drug inhibition escape leading to G12C resistance.[54] In view of these various intrinsic and adaptive resistance mechanisms, combination therapies are being tried in patients with KRAS G12C mutations for enhancing their clinical benefit in terms of survival outcomes and response rates.

  Role of Immunotherapy Top

The role of KRAS as a predictive marker for immune checkpoint inhibition remains elusive. A subgroup analysis of CheckMate 057 showed that patients who had KRAS-mutant NSCLC had a superior clinical benefit with nivolumab when compared to docetaxel.[55] A pooled analysis of five trials has also demonstrated superior outcomes in KRAS-mutant NSCLC when treated with immunotherapy in the second-line setting.[56] In the IMMUNOTARGET study,[57] these findings were corroborated, depicting a greater clinical benefit of immunotherapy in KRAS-mutant NSCLC when compared to EGFR-mutated NSCLC. However, the presence of co-occurring STK11 and KEAP1 mutations is a negative predictor for immunotherapy efficacy in KRAS-mutated tumors. A recent study demonstrated that sotorasib can potentiate immune rejection when used in combination with anti-programmed cell death 1 (PD1) drugs. This phase 1b trial (CodeBreaKTM 101, NCT04185883) is ongoing. In the KEYNOTE-042 study, patients with PD-ligand 1 (PD-L1)-positive advanced NSCLC were randomized to first-line pembrolizumab or platinum-based chemotherapy.[58] It showed that patients with KRAS G12C mutation demonstrated a higher PD-L1 tumor proportion score and tumor mutation burden, compared with patients with KRAS wild-type NSCLC. However, synergistic association of KRAS G12C inhibitors with immune checkpoint inhibitors needs further investigation.

  Conclusions and Future Perspectives Top

KRAS mutations are common across all malignancies including both solid tumors as well as hematolymphoid malignancies. A detailed knowledge of this is therefore essential not only for a better understanding of the disease process and the natural history but also for therapeutics and prognostics. CRISPR/Cas9-mediated technologies are being tried, as well as mRNA-based vaccines specifically targeting KRAS G12D/V are in trials (Phase I). An mRNA vaccine, mRNA-5671/V941, encoding G12D, G12V, G12C, and G13D as monotherapy or in combination with pembrolizumab is underway (NCT03948763).[59] Overall, the future for patients with KRAS-mutant tumors looks brighter compared to failed past efforts, and further studies are needed for better elucidation of resistance mechanisms, and upcoming therapeutic approaches. The administration of immunotherapy/chemoimmunotherapy has been studied in many trials as discussed above, depicting reasonable outcomes in the KRAS-mutated subgroup, when compared to other oncogene addicted tumors.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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