Combination therapy of first and third generation EGFR-TKIs for an advanced lung adenocarcinoma patient harboring EGFR mutations and amplification: a case report

: KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.

Download Full-text

P3.02-027 Lung Adenocarcinoma Patient with EGFR 19 Exon Insert Mutation: I740_K745insIPVAIK and Its Response to Icotinib: A Case Report

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2017.09.1557 ◽

2017 ◽

Vol 12 (11) ◽

pp. S2247

Author(s):

C. Xu ◽

W. Wang ◽

W. Zhuang ◽

Y. Chen ◽

G. Chen ◽

...

Keyword(s):

Case Report ◽

Lung Adenocarcinoma ◽

Lung Adenocarcinoma Patient

Download Full-text

Global proteome and phosphoproteome alterations in third generation EGFR TKI resistance reveal drug targets to circumvent resistance

10.1101/2020.07.04.187617 ◽

2020 ◽

Author(s):

Xu Zhang ◽

Tapan K. Maity ◽

Karen E. Ross ◽

Yue Qi ◽

Constance M. Cultraro ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Signaling Pathways ◽

Egfr Mutations ◽

Altered Expression ◽

Mesenchymal Transition ◽

Tki Resistance ◽

Egfr Tki ◽

Egfr Tkis ◽

Resistant Cells

AbstractLung cancer is the leading cause of cancer mortality worldwide. The treatment of lung cancer patients harboring mutant EGFR with orally administered EGFR TKIs has been a paradigm shift. Osimertinib and rociletinib are 3rd generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here, we have characterized the proteome and phosphoproteome of a series of isogenic EGFR mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs. To our knowledge, this is the most comprehensive proteomic dataset resource to date to investigate 3rd generation EGFR TKI resistance in lung adenocarcinoma. We have interrogated this unbiased global quantitative mass spectrometry dataset to uncover alterations in signaling pathways, reveal a proteomic signature of epithelial mesenchymal transition (EMT) and identify kinases and phosphatases with altered expression and phosphorylation in TKI resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition resulting in inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Furthermore, we performed anticorrelation analyses of this phosphoproteomic dataset with the published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures (LINCS) program to predict drugs with the potential to overcome EGFR TKI resistance. We identified dactolisib, a PI3K/mTOR inhibitor, which in combination with osimertinib overcomes resistance both in vitro and in vivo.One Sentence SummaryGlobal quantitative proteome and phosphoproteome analyses to examine altered signaling pathways in isogenic 3rd generation EGFR TKI sensitive and resistant cells.

Download Full-text