Aaron Vengalil

Introduction. NSCLC occurs as lung cancer cells proliferate uncontrollably and lead to the development of either benign or malignant tumors. Lung cancer represents one of the leading morbid cancers as it accounts for nearly 13% of all cancer diagnoses¹. The mortality of  lung cancers can be a result of cancer cells that acquire resistant alterations as a result of long exposure to therapy, which decreases the effectiveness of the treatment². NSCLCs have oncogenic driver mutations that confer sensitivity to tyrosine kinase inhibitors, which turns on kinase signaling pathways that presents a key event in the development of tumors³. Methods. CRISPR-dCAS9-SAM was utilized to induce endogenous FGFR1 genes, as well as biochemical EMT in HCC827 NSCLC cell lines⁴. Next-generation sequencing was used to investigate the presence of FGFR gene mutations in 143 tumors from patients with stage I, II or III SQCC and who had not been treated with chemotherapy or radiotherapy prior to surgery⁵. BT474 breast cancer cell line was treated with Lapatinib and IC50 values vs FGFR1 expression was observed in 27 breast cancer cell lines⁶. Human FGF-dependent H1581 NSCLC cells were exposed to increasing doses of NSC12 or erdafitinib and tumor proliferation was observed⁷. Several pools of HCC827 cells were treated with FGFR1 antagonist BGJ398 and EGFR inhibitor gefitinib, cell viability was subsequently observed⁸.  Results. EMT phenotype was observed with immunofluorescence analysis showed increased Vimentin and decreased E-cadherin expression compared to the original HCC827 cell line⁴. The ER cell line was then analyzed for FGFR1 expression. A 15 fold increase in FGFR expression was noted⁴. 143 Stage I, II, and III tumors were investigated for the presence of FGFR mutations. Of these mutations, 7% were somatic (nonheritable) and 9.8% were germline (heritable). mutations. Both mutations had a strong correlation with metastasis. Furthermore, disease-free survival and overall survival was worse with these FGFR⁵. FGFR expression increased in BT474 breast cancer cell lines was associated with a subsequent increase in Lap IC50 values or decrease in the potency of Lap⁶. Treatment with NSC12 or Erdafitinib reduced tumor cell proliferation⁷. Moreover, EGFR and FGFR inhibition with BGJ398 and Gefitinib prevents any emergence of drug tolerant persistent clones⁸. Conclusions. In NSCLC, FGFR expression is observed after an increase in EMT expression. This increase results in the unfavorable symptom of lung cancer metastasis. The further study of this mechanism is warranted to validate these results in new experimental settings. The findings that FGFR inhibition decreases lymph node metastasis represents the favorable probability that patients could benefit from FGFR targeted therapies. Future studies may further develop an FGFR-1 inhibitor that could become a valuable treatment for NSCLC patients.

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