Predictive and prognostic value of phosphorylated c‑KIT and PDGFRA in advanced non‑small cell lung cancer harboring ALK fusion

Abstract

Secondary KIT gene amplification leads to tyrosine kinase inhibitor resistance in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC). The presence of the 4q12 amplicon causes the activation of downstream mast/stem cell growth factor receptor Kit (c-Kit) or platelet-derived growth factor receptor α (PDGFRA) signaling pathways. Therefore, in the present study, the association between the functional proteins phosphorylated c-Kit (p-c-Kit) and phosphorylated PDGFRA (p-PDGFRA) and the prognosis of ALK fusion NSCLC was investigated. Advanced stage NSCLC samples with ALK fusion were tested for their p-c-Kit and p-PDGFRA content by immunohistochemical staining, and for its association with crizotinib efficacy and the survival of the patients. Of 64 eligible ALK-positive patients with NSCLC, 30 (46.9%) were p-c-Kit-positive and 10 (15.7%) were p-PDGFRA-positive. Brain metastases were more common in ALK-positive cases that were p-PDGFRA-positive compared with those who were p-PDGFRA-negative. ALK-positive patients treated with crizotinib, who exhibited high levels of p-c-Kit had significantly lower progression-free survival times than those with low levels. In addition, the patients with high levels of p-c-Kit exhibited lower overall survival times than those with low levels. Furthermore, multivariate analysis indicated that high levels of p-c-Kit in patients with ALK fusion was the only significant predictive factor for crizotinib efficacy and was a prognostic factor for poor overall survival time. However, no statistically significant difference was observed in the survival of patients with different p-PDGFRA levels. p-PDGFRA was more frequently expressed in the ALK-positive cases with brain metastasis. c-Kit signaling activation may be associated with poor efficacy of crizotinib and poor prognosis in advanced ALK fusion NSCLC.

A novel anti‐c‐Kit antibody–drug conjugate to treat wild‐type and activating‐mutant c‐Kit‐positive tumors

“…However, these interventions do not completely prevent the recurrence of the primary tumor at the same site, which may be because of the presence of therapy‐resistant cancer stem cells. The expression of c‐Kit, a biomarker of cancer stem cells, in ovarian cancer, non‐small cell lung carcinoma, prostate cancer, osteosarcoma, neuroblastoma, and endometrial cancer is correlated with poor prognosis [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. The SCF/c‐Kit signaling induces expression of ATP‐binding cassette G2 protein related to multi‐drug resistance through β‐catenin and consequently confers resistance to cisplatin, paclitaxel, and imatinib [ 26 ].…”

Prognostic Markers of Survival among Japanese Patients with Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer Receiving First-Line Alectinib

“…Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have been found to correlate with tumor progression. Phosphorylated stem cell growth factor receptor kit and PDGF-α have been reported as predictive and prognostic factors in ALK -positive NSCLC [ 37 ]. Platelets contain several growth factors, including PDGFs and transforming growth factor-β (TGF-β), which favor tumor progression [ 38 ].…”

Novel Resistance Mechanisms to Osimertinib Analysed by Whole-Exome Sequencing in Non-Small Cell Lung Cancer

“…PDGFRA, as a key factor in the PI3K-AKT-mTOR signalling pathway, plays a role in promoting cell proliferation, migration, and differentiation. 16 The CNVs of PDGFRA were associated with the survival time of ALK-TKIs in NSCLC, 17 and were also proven to cause ALK-TKI resistance in advanced NSCLC. 18 Although PDGFRA variations have been defined to be activated in many solid tumours and drug therapies, this is the first study to illuminate the influence of PDGFRA alteration on osimertinib resistance.…”