2002P - Genomic alterations of KEAP1/NFE2L2/CUL3(K/N/C) in Chinese lung cancer patients (pts)

Background

KEAP1/NFE2L2/CUL3 signaling pathway plays an important role in regulating the response to oxidative stress in lung cancer. Some studies have shown that K/N/C mutations promote resistance against chemotherapy and EGFR-TKI in lung cancer pts, while these pts may benefit from the clinical trial drug TORC1/2 inhibitor TAK-228. However, the mutational landscape of K/N/C in Chinese lung cancer pts remains unclear.

Methods

Totally 8312 Chinese pts with lung cancer were included in this retrospective study, the mutation characteristics of K/N/C gene in tumor tissues and/or liquid biopsy samples were analyzed by next-generation sequencing.

Results

7.2% (600/8312) lung cancer pts harbored K/N/C^MUT. Among them, the ratios of KEAP1, NFE2L2, CUL3 in Chinese pts were 4.63%, 2.08% and 0.81%, respectively. The most common mutations of KEAP1 were G9R (n = 12), R362Q (n = 9), R320L (n = 5) and D422N (n = 5), which were widely distributed from exon 2 to 6. In line with previous studies, hotspot mutations such as E79Q (n= 18), E79K (n= 14), R34Q (n = 9), R34P (n = 8), W24C (n = 8), D29H (n = 7), R34G (n = 6) were also the main mutation types of NFE2L2E gene in Chinese pts. Contrary to KEAP1, 80% of the NFE2L2E mutations were located in exon 2. No hotspot mutations were captured in CUL3, the primarily happened mutation was K722T. TP53 was the most frequent co-occurring mutant gene in lung cancer pts with K/N/C^MUT (the co-mutation frequencies with KEAP1, NFE2L2, CUL3 were 3.49%, 1.91%, and 0.65%, respectively). Other constant concomitant genes included LRP1B, FAT3, EGFR, CDKN2A, KMT2D, STK11, etc. Recently, mutations in the K/N/C pathway have been implicated as a potential mechanism of acquired EGFR-TKI resistance. Our analysis found that, 0.73% of the KEAP1-mutant pts co-mutated with common EGFR-TKI sensitive mutations, while the co-mutations happened respectively in 0.17% of the NFE2L2-mutant pts and 0.14% of CUL3-mutated pts. These pts may benefit from TORC1/2 inhibitor instead of EGFR-TKI.

Conclusions

So far, this is the largest genetic profile analysis of KEAP1/NFE2L2/CUL3 pathway in lung cancer. Genomic alterations of KEAP1/NFE2L2/CUL3 are common in lung cancer, making them highly promising therapeutic targets in these pts.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Department of Translational Medicine, Genetron Health (Beijing) Co.Ltd., Beijing, China.

Disclosure

All authors have declared no conflicts of interest.