Related Experiment Video
Updated: Dec 10, 2025
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden
D Marinelli1, M Mazzotta2, S Scalera3
1Department of Clinical and Molecular Medicine, Oncology Unit, Sant'Andrea Hospital, Sapienza University, Rome, Italy.
Background:
Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.
Patients And Methods:
KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.
Results:
On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.
Conclusions:
This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
Insights
Co-occurring mutations in KEAP1 and other genes identify lung adenocarcinoma patients unresponsive to immunotherapy. These co-mutant tumors have high tumor mutational burden and an immune-cold microenvironment, impacting survival outcomes.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Immune checkpoint inhibitors (ICIs) offer survival benefits for lung adenocarcinoma (LUAD) patients.
- However, immunotherapy efficacy shows significant patient variability, irrespective of PD-L1 or TMB.
- KEAP1 mutations are linked to poorer outcomes in LUAD patients treated with chemotherapy.
Purpose of the Study:
- To investigate if KEAP1 co-mutation patterns can identify LUAD patients with reduced immunotherapy response.
- To analyze the impact of coexisting somatic alterations on survival in ICI-treated LUAD.
Main Methods:
- KEAP1 mutational co-occurrences and interactions were analyzed in LUAD datasets.
- Survival outcomes in ICI-treated patients were assessed using blood-based (bNGS) and tissue-based (tNGS) sequencing cohorts.
- Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA).
Main Results:
- Four genes (KEAP1, PBRM1, SMARCA4, STK11) were associated with decreased immunotherapy efficacy.
- Tumors with coexisting mutations (CoMut) showed inferior survival compared to single-mutant (SM) and wild-type (WT) tumors in both cohorts.
- The CoMut subset had higher TMB, and this adverse effect persisted even in high TMB LUAD, with significant immunogenomic differences observed between CoMut and WT groups.
Conclusions:
- Coexisting alterations in specific genes define a LUAD subset unresponsive to immunotherapy.
- This subset exhibits high TMB and potentially an immune-cold microenvironment, contributing to their clinical course.
More Related Videos
09:38Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
07:42Patient-Derived Tumor Explants As a "Live" Preclinical Platform for Predicting Drug Resistance in Patients
Published on: February 7, 2021
Related Concept Videos
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:20Mismatch Repair
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
02:56Treatment Resistant Cancers
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:27Tumor Immunotherapy
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...