Work

Evolution and clinical impact of genetic epistasis within EGFR-mutant lung cancers

Year: 2017

Type: preprint

Abstract: The current understanding of tumorigenesis is largely centered on a monogenic driver oncogene model.This paradigm is incompatible with the prevailing clinical experience in most solid malignancies: monotherapy with a drug directed against an individual oncogenic driver typically results in incomplete clinical responses and eventual tumor progression [1][2][3][4][5][6][7] .By profiling the somatic genetic alterations present in over 2,000 cases of lung cancer, the leading cause of cancer mortality worldwide 8,9 , we show that combinations of functional genetic alterations, i.e. genetic collectives dominate the landscape of advanced-stage disease.We highlight this polygenic landscape and evolution of advanced-stage non-small cell lung cancer (NSCLC) through the spatial-temporal genomic profiling of 7 distinct tumor biopsy specimens and 6 plasma specimens obtained from an EGFR-mutant NSCLC patient at (1) initial diagnosis of early-stage disease, (2) metastatic progression, (3) sequential treatment and resistance to 2 EGFR inhibitors, (4) death.The comprehensive genomic analysis of this case, coupled with circulating free (cf) tumor DNA profiling of additional advancedstage EGFR-mutant NSCLC clinical cohorts with associated treatment responses uncovered features of evolutionary selection for multiple concurrent gene alterations: including the presence of EGFR inhibitorsensitive (EGFR L858R ;EGFR exon19del ) or inhibitor-resistant (EGFR T790M ;EGFR C797S ) forms of oncogenic EGFR along with cell cycle gene alterations (e.g. in CDK4/6, CCNE1, RB1) and activating alterations in WNT/βcatenin and PI3K pathway genes, which our data suggest can cooperatively impart non-redundant functions to limit EGFR targeted therapy response and/or promote tumor progression.Moreover, evidence of an unanticipated parallel evolution of both EGFR T790M and two distinct forms of oncogenic PIK3CA was observed.Our study provides a large-scale clinical and genetic dataset of advanced-stage EGFR-mutant NSCLC, a rationale for specific polytherapy strategies such as EGFR and CDK4/6 inhibitor co-treatment to potentially enhance clinical outcomes, and prompts a re-evaluation of the prevailing paradigm of monogenic-based molecular stratification for targeted therapy.Instead, our findings highlight an alternative model of genetic collectives that operate through epistasis to drive lung cancer progression and therapy resistance. Main text.The identification of specific, therapeutically targetable genetic alterations that drive the growth of many cancers including non-small cell lung cancer (NSCLC), the major subtype of lung cancer, has revolutionized the diagnosis and treatment of patients.The clinical success of genetically-targeted therapies such as EGFR, ALK, ROS-1 and BRAF inhibitors [1][2][3][4][5][6][7]10,11 has led to the current monogenic driver oncogene model of tumorigenesis, wherein advanced-stage NSCLC patients are selected for a gene-targeted monotherapy based on the identification of an individual specific driver alteration present in the tumor (e.g. mutant EGFR or an ALK gene rearrangement). This odel is incompatible with the prevailing clinical experience in most advancedstage solid malignancies including NSCLC, wherein monotherapy with a drug directed against a particular oncogenic driver protein, while typically more effective than cytotoxic chemotherapy, generally results in incomplete responses and eventual tumor progression in patients (reviewed in 12 ).In contrast to this monogenic model of disease pathogenesis and treatment, it is possible that advanced-stage NSCLCs exhibit a polygenic

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/117291