bims-tumhet 2021-11-14 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2021–11–14
fourteen papers selected by
Sergio Marchini, Humanitas Research

Options for the Treatment of Mucinous Ovarian Carcinoma.
Circulating Biomarkers in Breast Cancer.
Treatment Perspectives for Ovarian Cancer in Europe and the United States: Initial Therapy and Platinum-Sensitive Recurrence after PARP Inhibitors or Bevacizumab Therapy.
Recognition of DNA Methylation Molecular Features for Diagnosis and Prognosis in Gastric Cancer.
DNA methylation-based classifier and gene expression signatures detect BRCAness in osteosarcoma.
Longitudinal Copy Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis and Follow-Up.
The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis.
Genomic Instability of Circulating Tumor DNA as a Prognostic Marker for Pancreatic Cancer Survival: A Prospective Cohort Study.
Ploidy and recombination proficiency shape the evolutionary adaptation to constitutive DNA replication stress.
Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact.
The Single-Cell Sequencing: A Dazzling Light Shining on the Dark Corner of Cancer.
Adjuvant Chemotherapy May Not Be Necessary for Women with Stage IC1 Epithelial Ovarian Cancer.
Low-Coverage Whole Genome Sequencing Using Laser Capture Microscopy with Combined Digital Droplet PCR: An Effective Tool to Study Copy Number and Kras Mutations in Early Lung Adenocarcinoma Development.
Diverse alterations associated with resistance to KRAS(G12C) inhibition.

Curr Treat Options Oncol. 2021 Nov 13. 22(12): 114

Options for the Treatment of Mucinous Ovarian Carcinoma.

Olivia Craig, Carolina Salazar, Kylie L Gorringe.

   OPINION STATEMENT: Complete surgical resection is the gold-standard treatment for all mucinous ovarian carcinoma (MOC) cases. Advanced-stage disease is often additionally treated with adjuvant platinum-based chemotherapy; however, these were developed largely against the more common high-grade serous ovarian carcinoma and have low efficacy in treating MOC. More effective therapeutics are needed to treat late-stage and platinum-resistant tumors; however, traditional drug development and clinical trial paradigms are a major challenge for such a rare disease. New approaches to support evidence-based treatment decisions are required, such as registry trials. Recently, a number of targeted therapies have emerged as viable treatment options in other cancer types, and for some of these, the actionable tumor mutations are also seen in MOC. Thus, a promising alternative approach to provide benefit to current MOC patients involves DNA sequencing to identify a tumor's unique mutational profile and allow matching to available targeted agents. Such a pipeline can involve special approval to administer a drug already approved for clinical use in other cancer types to a given MOC patient, or their inclusion in existing ongoing clinical trials, such as basket trials encompassing patients with tumors from a range of anatomical sites. Implementation of such personalized medicine can be boosted using improved pre-clinical models, where through a clinical research collaboration a patient's own tumor cells can be used to a test a range of putative therapies prior to administration in the clinic, enabling selection of the available pharmaceutical/s that give any given patient the best possible chance of cancer remission.

Keywords:  Debulking surgery; Epithelial ovarian cancer; Mucinous ovarian carcinoma; Platinum-based chemotherapy; Targeted therapies; Treatment

DOI:  https://doi.org/10.1007/s11864-021-00904-6
Clin Breast Cancer. 2021 Sep 22. pii: S1526-8209(21)00264-0. [Epub ahead of print]

Circulating Biomarkers in Breast Cancer.

Katelyn N Seale, Katherine H R Tkaczuk.

Breast cancer management has progressed immensely over the decades, but the disease is still a major source of morbidity and mortality worldwide. Even with enhanced imaging detection and tissue biopsy capabilities, disease can progress on an ineffective treatment before additional information is obtained through standard methods of response evaluation, including the RECIST 1.1 criteria, widely used for assessment of treatment response and benefit from therapy.6 Circulating biomarkers have the potential to provide valuable insight into disease progression and response to therapy, and they can serve to identify actionable mutations and tumor characteristics that can direct therapy. These biomarkers can be collected at higher frequencies than imaging or tissue sampling, potentially allowing for more informed management. This review will evaluate the roles of circulating biomarkers in breast cancer, including the serum markers Carcinoembryonic antigen CA15-3, CA27-29, HER2 ECD, and investigatory markers such as GP88; and the components of the liquid biopsy, including circulating tumor cells, cell free DNA/DNA methylation, circulating tumor DNA, and circulating microRNA.

DOI: https://doi.org/10.1016/j.clbc.2021.09.006
Curr Oncol Rep. 2021 Nov 09. 23(12): 148

Treatment Perspectives for Ovarian Cancer in Europe and the United States: Initial Therapy and Platinum-Sensitive Recurrence after PARP Inhibitors or Bevacizumab Therapy.

Alexandra Lainé, Travis T Sims, Olivia Le Saux, Isabelle Ray-Coquard, Robert L Coleman.

   PURPOSE OF REVIEW: Although the survival rate of patients with ovarian cancer (OC) has significantly improved, OC is still one of the most common causes of gynecologic cancer death in women worldwide. The current advances in primary treatment are based on recent regulatory approvals and recurrency of such treatments, challenging the development of a unified approach to care. Herein, we examine how integration of these new approaches is applied to patient's treatment.
RECENT FINDINGS: We and others have recently reported clinical trials using bevacizumab and/or inhibitors of Poly (ADP-ribose) polymerase (PARP), which have greatly affected the change in first-line treatments for OC. As first-line therapy has evolved, therapeutic agents once designated for recurrent disease are increasingly being incorporated, changing our standard of care following previously indexed trials. Here, we provide an overview of the current treatment for OC patients, and we highlight practice patterns in Europe and in the USA with corresponding opinions on current and future treatments for platinum-sensitive recurrent OC.

Keywords:  Anti-angiogenic; Maintenance therapy; Ovarian cancer; PARP inhibitors; Platinum-sensitive

DOI:  https://doi.org/10.1007/s11912-021-01128-5
Front Genet. 2021 ;12 758926

Recognition of DNA Methylation Molecular Features for Diagnosis and Prognosis in Gastric Cancer.

Donghui Liu, Long Li, Liru Wang, Chao Wang, Xiaowei Hu, Qingxin Jiang, Xuyao Wang, Guiqin Xue, Yu Liu, Dongbo Xue.

  Background: The management of gastric cancer (GC) still lacks tumor markers with high specificity and sensitivity. The goal of current research is to find effective diagnostic and prognostic markers and to clarify their related mechanisms. Methods: In this study, we integrated GC DNA methylation data from publicly available datasets obtained from TCGA and GEO databases, and applied random forest and LASSO analysis methods to screen reliable differential methylation sites (DMSs) for GC diagnosis. We constructed a diagnostic model of GC by logistic analysis and conducted verification and clinical correlation analysis. We screened credible prognostic DMSs through univariate Cox and LASSO analyses and verified a prognostic model of GC by multivariate Cox analysis. Independent prognostic and biological function analyses were performed for the prognostic risk score. We performed TP53 correlation analysis, mutation and prognosis analysis on eleven-DNA methylation driver gene (DMG), and constructed a multifactor regulatory network of key genes. Results: The five-DMS diagnostic model distinguished GC from normal samples, and diagnostic risk value was significantly correlated with grade and tumor location. The prediction accuracy of the eleven-DMS prognostic model was verified in both the training and validation datasets, indicating its certain potential for GC survival prediction. The survival rate of the high-risk group was significantly lower than that of the low-risk group. The prognostic risk score was an independent risk factor for the prognosis of GC, which was significantly correlated with N stage and tumor location, positively correlated with the VIM gene, and negatively correlated with the CDH1 gene. The expression of CHRNB2 decreased significantly in the TP53 mutation group of gastric cancer patients, and there were significant differences in CCDC69, RASSF2, CHRNB2, ARMC9, and RPN1 between the TP53 mutation group and the TP53 non-mutation group of gastric cancer patients. In addition, CEP290, UBXN8, KDM4A, RPN1 had high frequency mutations and the function of eleven-DMG mutation related genes in GC patients is widely enriched in multiple pathways. Conclusion: Combined, the five-DMS diagnostic and eleven-DMS prognostic GC models are important tools for accurate and individualized treatment. The study provides direction for exploring potential markers of GC.

Keywords:  DNA methylation; diagnosis; gastric cancer; mutation; prognosis; tumor marker

DOI:  https://doi.org/10.3389/fgene.2021.758926
PLoS Comput Biol. 2021 Nov;17(11): e1009562

DNA methylation-based classifier and gene expression signatures detect BRCAness in osteosarcoma.

Maxim Barenboim, Michal Kovac, Baptiste Ameline, David T W Jones, Olaf Witt, Stefan Bielack, Stefan Burdach, Daniel Baumhoer, Michaela Nathrath.

Although osteosarcoma (OS) is a rare cancer, it is the most common primary malignant bone tumor in children and adolescents. BRCAness is a phenotypical trait in tumors with a defect in homologous recombination repair, resembling tumors with inactivation of BRCA1/2, rendering these tumors sensitive to poly (ADP)-ribose polymerase inhibitors (PARPi). Recently, OS was shown to exhibit molecular features of BRCAness. Our goal was to develop a method complementing existing genomic methods to aid clinical decision making on administering PARPi in OS patients. OS samples with DNA-methylation data were divided to BRCAness-positive and negative groups based on the degree of their genomic instability (n = 41). Methylation probes were ranked according to decreasing variance difference between two groups. The top 2000 probes were selected for training and cross-validation of the random forest algorithm. Two-thirds of available OS RNA-Seq samples (n = 17) from the top and bottom of the sample list ranked according to genome instability score were subjected to differential expression and, subsequently, to gene set enrichment analysis (GSEA). The combined accuracy of trained random forest was 85% and the average area under the ROC curve (AUC) was 0.95. There were 449 upregulated and 1,079 downregulated genes in the BRCAness-positive group (fdr < 0.05). GSEA of upregulated genes detected enrichment of DNA replication and mismatch repair and homologous recombination signatures (FWER < 0.05). Validation of the BRCAness classifier with an independent OS set (n = 20) collected later in the course of study showed AUC of 0.87 with an accuracy of 90%. GSEA signatures computed for this test set were matching the ones observed in the training set enrichment analysis. In conclusion, we developed a new classifier based on DNA-methylation patterns that detects BRCAness in OS samples with high accuracy. GSEA identified genome instability signatures. Machine-learning and gene expression approaches add new epigenomic and transcriptomic aspects to already established genomic methods for evaluation of BRCAness in osteosarcoma and can be extended to cancers characterized by genome instability.

DOI: https://doi.org/10.1371/journal.pcbi.1009562
Clin Cancer Res. 2021 Nov 10. pii: clincanres.2291.2021. [Epub ahead of print]

Longitudinal Copy Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis and Follow-Up.

Gitta Boons, Timon Vandamme, Laura Mariën, Willem Lybaert, Geert Roeyen, Tim Rondou, Konstantinos Papadimitriou, Katrien Janssens, Bart Op de Beeck, Marc Simoens, Wim Demey, Isabel Dero, Guy Van Camp, Marc Peeters, Ken Op de Beeck.

PURPOSE: As non-invasive biomarkers are an important unmet need for neuroendocrine neoplasms (NENs), biomarker potential of genome-wide molecular profiling of plasma cell-free DNA (cfDNA) was prospectively studied in NEN patients.
EXPERIMENTAL DESIGN: Longitudinal plasma samples were collected from well-differentiated, metastatic gastroenteropancreatic and lung NEN patients. cfDNA was subjected to shallow whole-genome sequencing to detect genome-wide copy number alterations (CNAs) and estimate circulating tumor DNA (ctDNA) fraction, and correlated to clinicopathological and survival data. To differentiate pancreatic NENs (PNENs) from pancreatic adenocarcinomas (PAADs) using liquid biopsies, a classification model was trained using tissue-based CNAs and validated in cfDNA.
RESULTS: 195 cfDNA samples from 43 NEN patients were compared to healthy control cfDNA (N=100). Plasma samples from PNEN patients (N=21) were used for comparison to publicly available PNEN tissue (N=98), PAAD tissue (N=109) and PAAD cfDNA (N=96) data. 30% of the cfDNA samples contained ctDNA and 44% of the patients had at least one ctDNA-positive (ctDNA+) sample. CNAs detected in cfDNA were highly specific for NENs and the classification model could distinguish PAAD and PNEN cfDNA samples with a sensitivity, specificity and area under the curve of 62%, 86% and 79%, respectively. ctDNA-positivity was associated with higher WHO grade, primary tumor location and higher chromogranin A and neuron-specific enolase values. Overall survival was significantly worse for ctDNA+ patients and increased ctDNA fractions were associated with poorer progression-free survival.
CONCLUSIONS: Sequential genome-wide profiling of plasma cfDNA is a novel, non-invasive biomarker with high specificity for diagnosis, prognosis and follow-up in metastatic NENs.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-2291
Mol Cancer. 2021 Nov 10. 20(1): 145

The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis.

Ana Luiza Drumond-Bock, Magdalena Bieniasz.

  High-grade serous ovarian carcinoma (HGSOC) is the most aggressive type of ovarian cancer, often diagnosed at advanced stages. Molecularly, HGSOC shows high degree of genomic instability associated with large number of genetic alterations. BRD4 is the 4th most amplified gene in HGSOC, which correlates with poor patients' prognosis. BRD4 is constitutively expressed and generates two proteins, BRD4 long (BRD4-L) and BRD4 short (BRD4-S). Both isoforms contain bromodomains that bind to lysine-acetylated histones. Amongst other functions, BRD4 participates in chromatin organization, acetylation of histones, transcriptional control and DNA damage repair. In cancer patients with amplified BRD4, the increased activity of BRD4 is associated with higher expression of oncogenes, such as MYC, NOTCH3 and NRG1. BRD4-driven oncogenes promote increased tumor cells proliferation, genetic instability, epithelial-mesenchymal transition, metastasis and chemoresistance. Ablation of BRD4 activity can be successfully achieved with bromodomain inhibitors (BETi) and degraders, and it has been applied in pre-clinical and clinical settings. Inhibition of BRD4 function has an effective anti-cancer effect, reducing tumor growth whether ablated by single agents or in combination with other drugs. When combined with standard chemotherapy, BETi are capable of sensitizing highly resistant ovarian cancer cell lines to platinum drugs. Despite the evidence that BRD4 amplification in ovarian cancer contributes to poor patient prognosis, little is known about the specific mechanisms by which BRD4 drives tumor progression. In addition, newly emerging data revealed that BRD4 isoforms exhibit contradicting functions in cancer. Therefore, it is paramount to expand studies elucidating distinct roles of BRD4-L and BRD4-S in HGSOC, which has important implications on development of therapeutic approaches targeting BRD4.

Keywords:  BET inhibitors; BRD4; Gene amplification; High-grade serous ovarian carcinoma

DOI:  https://doi.org/10.1186/s12943-021-01424-5
Cancers (Basel). 2021 Oct 30. pii: 5466. [Epub ahead of print]13(21):

Genomic Instability of Circulating Tumor DNA as a Prognostic Marker for Pancreatic Cancer Survival: A Prospective Cohort Study.

Sang Myung Woo, Min Kyeong Kim, Boram Park, Eun-Hae Cho, Tae-Rim Lee, Chang-Seok Ki, Kyong-Ah Yoon, Yun-Hee Kim, Wonyoung Choi, Do Yei Kim, Jin-Hyeok Hwang, Jae Hee Cho, Sung-Sik Han, Woo Jin Lee, Sang-Jae Park, Sun-Young Kong.

  Genomic instability of circulating tumor DNA (ctDNA) as a prognostic biomarker has not been evaluated in pancreatic cancer. We investigated the role of the genomic instability index of ctDNA in pancreatic ductal adenocarcinoma (PDAC). We prospectively enrolled 315 patients newly diagnosed with resectable (n = 110), locally advanced (n = 78), and metastatic (n = 127) PDAC from March 2015 through January 2020. Low-depth whole-genome cell-free DNA sequencing identified genome-wide copy number alterations using instability score (I-score) to reflect genome-wide instability. Plasma cell-free and matched tumor tissue DNA from 15 patients with resectable pancreatic cancer was sequenced to assess the concordance of chromosomal copy number alteration profiles. Associations of I-score with clinical factors or survival were assessed. Seventy-six patients had high genomic instability with I-score > 7.3 in pre-treatment ctDNA; proportions of high I-score were 5.5%, 5.1%, and 52% in resectable, locally advanced, and metastatic stages, respectively. Correlation coefficients between Z-scores of plasma and tissue DNA at segment resolution were high (r2 = 0.82). Univariable analysis showed the association of I-score with progression-free survival in each stage. Multivariable analyses demonstrated that clinical stage-adjusted I-scores were significant factors for progression-free and overall survival. In these patients, ctDNA genomic I-scores provided prognostic information relevant to progression-free survival in each clinical stage.

Keywords:  circulating tumor DNA; genomic instability; genomic instability index; instability score; outcome prediction; pancreatic cancer; pancreatic ductal adenocarcinoma; prognostic biomarker

DOI:  https://doi.org/10.3390/cancers13215466
PLoS Genet. 2021 Nov 09. 17(11): e1009875

Ploidy and recombination proficiency shape the evolutionary adaptation to constitutive DNA replication stress.

Marco Fumasoni, Andrew W Murray.

In haploid budding yeast, evolutionary adaptation to constitutive DNA replication stress alters three genome maintenance modules: DNA replication, the DNA damage checkpoint, and sister chromatid cohesion. We asked how these trajectories depend on genomic features by comparing the adaptation in three strains: haploids, diploids, and recombination deficient haploids. In all three, adaptation happens within 1000 generations at rates that are correlated with the initial fitness defect of the ancestors. Mutations in individual genes are selected at different frequencies in populations with different genomic features, but the benefits these mutations confer are similar in the three strains, and combinations of these mutations reproduce the fitness gains of evolved populations. Despite the differences in the selected mutations, adaptation targets the same three functional modules despite differences in genomic features, revealing a common evolutionary response to constitutive DNA replication stress.

DOI: https://doi.org/10.1371/journal.pgen.1009875
Cancers (Basel). 2021 Oct 26. pii: 5364. [Epub ahead of print]13(21):

Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact.

Natasha Honoré, Rachel Galot, Cédric van Marcke, Nisha Limaye, Jean-Pascal Machiels.

  One reason why some patients experience recurrent disease after a curative-intent treatment might be the persistence of residual tumor cells, called minimal residual disease (MRD). MRD cannot be identified by standard radiological exams or clinical evaluation. Tumor-specific alterations found in the blood indirectly diagnose the presence of MRD. Liquid biopsies thus have the potential to detect MRD, allowing, among other things, the detection of circulating tumor DNA (ctDNA), circulating tumor cells (CTC), or tumor-specific microRNA. Although liquid biopsy is increasingly studied, several technical issues still limit its clinical applicability: low sensitivity, poor standardization or reproducibility, and lack of randomized trials demonstrating its clinical benefit. Being able to detect MRD could give clinicians a more comprehensive view of the risk of relapse of their patients and could select patients requiring treatment escalation with the goal of improving cancer survival. In this review, we are discussing the different methodologies used and investigated to detect MRD in solid cancers, their respective potentials and issues, and the clinical impacts that MRD detection will have on the management of cancer patients.

Keywords:  ctDNA; liquid biopsy; minimal residual disease

DOI:  https://doi.org/10.3390/cancers13215364
Front Oncol. 2021 ;11 759894

The Single-Cell Sequencing: A Dazzling Light Shining on the Dark Corner of Cancer.

Jing Li, Nan Yu, Xin Li, Mengna Cui, Qie Guo.

  Tumorigenesis refers to the process of clonal dysplasia that occurs due to the collapse of normal growth regulation in cells caused by the action of various carcinogenic factors. These "successful" tumor cells pass on the genetic templates to their generations in evolutionary terms, but they also constantly adapt to ever-changing host environments. A unique peculiarity known as intratumor heterogeneity (ITH) is extensively involved in tumor development, metastasis, chemoresistance, and immune escape. An understanding of ITH is urgently required to identify the diversity and complexity of the tumor microenvironment (TME), but achieving this understanding has been a challenge. Single-cell sequencing (SCS) is a powerful tool that can gauge the distribution of genomic sequences in a single cell and the genetic variability among tumor cells, which can improve the understanding of ITH. SCS provides fundamental ideas about existing diversity in specific TMEs, thus improving cancer diagnosis and prognosis prediction, as well as improving the monitoring of therapeutic response. Herein, we will discuss advances in SCS and review SCS application in tumors based on current evidence.

Keywords:  cancer; intratumor heterogeneity; single tumor cell; single-cell sequencing; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.759894
Curr Med Sci. 2021 Nov 10.

Adjuvant Chemotherapy May Not Be Necessary for Women with Stage IC1 Epithelial Ovarian Cancer.

Dong-Mei Deng, Qiu-Yue Liao, Jie Yang, Jing Chen, Ge Chen, Hua-Lin Bai, Bo Zhang, Ke-Zhen Li.

   OBJECTIVE: To determine whether adjuvant chemotherapy improves the prognoses in women with stage IC1 epithelial ovarian cancer (EOC).
METHODS: All eligible women diagnosed with stage IC1 EOC from 2003 to 2019 in Tongji Hospital were included. Patient characteristics, tumor features, surgical types, and chemotherapeutic treatments were collected. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate progression-free survival (PFS) and overall survival (OS).
RESULTS: Of the 140 patients (median age: 47 years old), 13 patients did not receive chemotherapy, and 127 received adjuvant chemotherapy. Kaplan-Meier analysis indicated that adjuvant chemotherapy offered no obvious improvements in PFS or OS. Subgroup analysis was conducted to adjust for the significant difference in incomplete staging surgery between the two groups, and chemotherapy still showed no benefit for survival. Cox regression analysis indicated that incomplete staging surgery was a risk factor for a worse PFS and that adjuvant chemotherapy remained unrelated to the prognosis. The patients were further divided based on the National Comprehensive Cancer Network recommendations: patients for whom observation is optional and chemotherapy would not improve the prognosis; and patients for whom chemotherapy is recommended. The results showed that postoperative chemotherapy had little correlation with survival.
CONCLUSION: Our study suggests that postoperative chemotherapy may be unnecessary for patients with stage IC1 EOC. According to our results, incomplete staging surgery is a significant risk factor for PFS.

Keywords:  adjuvant chemotherapy; epithelial ovarian cancer; intraoperative rupture; overall survival; progression-free survival

DOI:  https://doi.org/10.1007/s11596-021-2462-7
Int J Mol Sci. 2021 Nov 06. pii: 12034. [Epub ahead of print]22(21):

Low-Coverage Whole Genome Sequencing Using Laser Capture Microscopy with Combined Digital Droplet PCR: An Effective Tool to Study Copy Number and Kras Mutations in Early Lung Adenocarcinoma Development.

Elizabeth A Mickler, Huaxin Zhou, Tzu L Phang, Mark W Geraci, Robert S Stearman, Catherine R Sears.

  Defining detailed genomic characterization of early tumor progression is critical to identifying key regulators and pathways in carcinogenesis as potentially druggable targets. In human lung cancer, work to characterize early cancer development has mainly focused on squamous cancer, as the earliest lesions are more proximal in the airways and often accessible by repeated bronchoscopy. Adenocarcinomas are typically located distally in the lung, limiting accessibility for biopsy of pre-malignant and early stages. Mouse lung cancer models recapitulate many human genomic features and provide a model for tumorigenesis with pre-malignant atypical adenomatous hyperplasia and in situ adenocarcinomas often developing contemporaneously within the same animal. Here, we combined tissue characterization and collection by laser capture microscopy (LCM) with digital droplet PCR (ddPCR) and low-coverage whole genome sequencing (LC-WGS). ddPCR can be used to identify specific missense mutations in Kras (Kirsten rat sarcoma viral oncogene homolog, here focused on Kras Q61) and estimate the percentage of mutation predominance. LC-WGS is a cost-effective method to infer localized copy number alterations (CNAs) across the genome using low-input DNA. Combining these methods, the histological stage of lung cancer can be correlated with appearance of Kras mutations and CNAs. The utility of this approach is adaptable to other mouse models of human cancer.

Keywords:  Kras; carcinogenesis; copy number alterations; lung cancer; mouse

DOI:  https://doi.org/10.3390/ijms222112034
Nature. 2021 Nov 10.

Diverse alterations associated with resistance to KRAS(G12C) inhibition.

Yulei Zhao, Yonina R Murciano-Goroff, Jenny Y Xue, Agnes Ang, Jessica Lucas, Trang T Mai, Arnaud F Da Cruz Paula, Anne Y Saiki, Deanna Mohn, Pragathi Achanta, Ann E Sisk, Kanika S Arora, Rohan S Roy, Dongsung Kim, Chuanchuan Li, Lee P Lim, Mark Li, Amber Bahr, Brian R Loomis, Elisa de Stanchina, Jorge S Reis-Filho, Britta Weigelt, Michael Berger, Gregory Riely, Kathryn C Arbour, J Russell Lipford, Bob T Li, Piro Lito.

Inactive state-selective KRAS(G12C) inhibitors1-8 demonstrate a 30-40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.

DOI: https://doi.org/10.1038/s41586-021-04065-2