Integrated genomic approaches identify upregulation of <i>SCRN1</i> as a novel mechanism associated with acquired resistance to erlotinib in PC9 cells harboring oncogenic EGFR mutation

Cho

et al. 2019

Intl Journal of Cancer

Self Cite

Somatic mutations of epidermal growth factor receptor (EGFR) occur in ~3% of colorectal cancer (CRC) patients. Here, through systematic functional screening of 21 recurrent EGFR mutations selected from public data sets, we show that 11 colon cancer‐derived EGFR mutants (G63R, E114K, R165Q, R222C, S492R, P596L, K708R, E709K, G719S, G724S and L858R) are oncogenic and able to transform cells in a ligand‐independent manner. We demonstrate that cellular transformation by these mutants requires receptor dimerization. Importantly, the EGF‐induced and constitutive oncogenic potential of these EGFR mutants are inhibited by cetuximab or panitumumab in vivo and in vitro. Taken together, we propose that a subset of EGFR mutations can serve as genomic predictors for response to anti‐EGFR antibodies and that metastatic CRC patients with such mutations may benefit from these drugs as part of the first‐line therapy.

Section: Methodsmentioning

confidence: 99%

Section: Anchorage-independent Growth Assaymentioning

confidence: 99%

Colorectal adenocarcinoma‐derived EGFR mutants are oncogenic and sensitive to EGFR‐targeted monoclonal antibodies, cetuximab and panitumumab

Cho

et al. 2019

Intl Journal of Cancer

Self Cite

“…However, the disease inevitably acquires resistance to EGFR TKIs. Mechanisms of this resistance include the development of a second-site EGFR resistance mutation ( T790M ); the activation of parallel signaling pathways, including cMET, HER2, FGFR, Mer and AXL; up regulation of SCRN1; epithelial–mesenchymal transition (EMT); and small cell transformation [4–11]. Drugs that inhibit glutaminase C, JAK, Mer and Src are effective in some EGFR TKI resistance models [8–10, 12].…”

Section: Introductionmentioning

confidence: 99%

Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations

et al. 2016

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with activating EGFR mutations, but resistance is inevitable. Mechanisms of acquired resistance include T790M mutations and epithelial–mesenchymal transition (EMT). One potential strategy for overcoming this resistance is the inhibition of polo-like kinase 1 (PLK1) based on our previous studies showing that mesenchymal NSCLC cell lines are more sensitive to PLK1 inhibition than epithelial cell lines. To determine the extent to which PLK1 inhibition overcomes EGFR TKI resistance we measured the effects of the PLK1 inhibitor volasertib alone and in combination with the EGFR inhibitor erlotinib in vitro and in vivo in EGFR mutant NSCLC cell lines with acquired resistance to erlotinib. Two erlotinib-resistant cell lines that underwent EMT had higher sensitivity to volasertib, which caused G2/M arrest and apoptosis, than their parental cells. In all NSCLC cell lines with T790M mutations, volasertib markedly reduced erlotinib resistance. All erlotinib-resistant NSCLC cell lines with T790M mutations had higher sensitivity to erlotinib plus volasertib than to erlotinib alone, and the combination treatment caused G2/M arrest and apoptosis. Compared with either agent alone, the combination treatment also caused significantly more DNA damage and greater reductions in tumor size. Our results suggest that PLK1 inhibition is clinically effective against NSCLC that becomes resistant to EGFR inhibition through EMT or the acquisition of a T790M mutation. These results uncover new functions of PLK1 inhibition in the treatment of NSCLC with acquired resistance to EGFR TKIs.

“…GAPDH was used as the internal standard for normalization. The primer sequences used are as follows; TNS4 primer set (forward: 5′-CACCATGAAGTTCGTGATG-3′; reverse: 5′-CGGTATGAAGAGCTGTCC-3′), GAPDH primer set (forward: 5′-GGTGTGAACCATGAGAAGTATGA-3′; reverse: 5′-GAGTCCTTCCACGATACCAAAG-3′) [30,31].…”

Section: Methodsmentioning

confidence: 99%

Whole Transcriptome Analysis Identifies TNS4 as a Key Effector of Cetuximab and a Regulator of the Oncogenic Activity of KRAS Mutant Colorectal Cancer Cell Lines

Kang

et al. 2019

Cells

The targeting of activated epidermal growth factor receptor (EGFR) with therapeutic anti-EGFR monoclonal antibodies (mAbs) such as cetuximab and panitumumab has been used as an effective strategy in the treatment of colorectal cancer (CRC). However, its clinical efficacy occurs only in a limited number of patients. Here, we performed whole-transcriptome analysis in xenograft mouse tumors induced by KRASG12D mutation-bearing LS174T CRC cells following treatment with either cetuximab or PBS. Through integrated analyses of differential gene expression with TCGA and CCLE public database, we identified TNS4, overexpressed in CRC patients and KRAS mutation-harboring CRC cell lines, significantly downregulated by cetuximab. While ablation of TNS4 expression via shRNA results in significant growth inhibition of LS174T, DLD1, WiDr, and DiFi CRC cell lines, conversely, its ectopic expression increases the oncogenic growth of these cells. Furthermore, TNS4 expression is transcriptionally regulated by MAP kinase signaling pathway. Consistent with this finding, selumetinib, a MEK1/2 inhibitor, suppressed oncogenic activity of CRC cells, and this effect is more profound in combination with cetuximab. Altogether, we propose that TNS4 plays a crucial role in CRC tumorigenesis, and that suppression of TNS4 would be an effective therapeutic strategy in treating a subset of cetuximab-refractory CRC patients including KRAS activating mutations.