Abstract 1182P
Background
PTPN11 encodes the SHP2 protein tyrosine phosphatase which regulates cell survival and proliferation primarily by activating the RAS-MAPK signaling pathway. Abnormal expression or activation of SHP2 is associated with various tumorigenesis, such as lung cancer. Thus, targeting SHP2 has emerged as a promising oncology therapy. Several SHP2 allosteric inhibitors, such as ICP-189 and RMC-4630, have been entered into clinical trials. However, the mutational landscape of PTPN11 remains unclear, we systematically analyzed the genomic profiling of PTPN11 in Chinese lung cancer patients (pts).
Methods
Totally 28686 Chinese lung cancer pts were included in this retrospective study, the mutation (mut) characteristics of PTPN11 in tumor tissues and/or liquid biopsy samples and their co-mut with RTKs and KRAS were analyzed by next generation sequencing.
Results
The mut frequency(freq) of PTPN11 in Chinese lung cancer pts was 0.67% (191/28686), and the most common muts were G503V (n =14), Y515N (n=10), Y511N (n=8) and amplification (n=10), where G503V was a reported hotspot activating mut. SHP2 has been reported as a key node for RTKs signaling pathways, and its inhibitors can overcome multiple therapeutic resistance in NSCLC. Our analysis found the co-mut freq of PTPN11 with RTK family members EGFR, ERBBB2, MET, FGFR1/2/3 were 0.83% (104/12463), 3% (51/1701), 5.81% (58/999), 7.41% (45/607), 12.32% (44/357) and 6.09% (40/657) in Chinese lung cancer pts, respectively, while co-occurred with ALK, RET, ROS1 and NTRK fusion were 1.05% (10/956), 0.35% (1/287), 0.52% (1/191) and 0 (0/25). Targeting SHP2 may be a therapy strategy for TKI resistance in these pts. Early clinical trials have found that the combination of SHP2 and MEK/KRAS-G12C inhibitors can effectively block the MAPK pathway, and lung cancer pts with RAS-mut are more benefit from the therapy. Clinical data showed the co-mut freq of KRAS-G12C with PTPN11 was 0.95% (8/842) while MEK1/2, BRAF were 11.28% (38/337) and 4.13% (63/1526) in Chinese lung cancer pts.
Conclusions
The mutational characteristics of PTPN11 in Chinese lung cancer population was first revealed in this study, which provides a broad range of scenarios for the future clinical application of SHP2 inhibitors in lung cancer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
C. Wang, Q. Liu, D. Wang, T. Ma: Financial Interests, Institutional, Full or part-time Employment: Genetron Health. All other authors have declared no conflicts of interest.