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  • br CSC Biomarkers Related to Clinical

    2020-08-28


    CSC Biomarkers Related to Clinical Outcome to EGFR Inhibition
    To test whether our findings were clinically relevant, we inves-tigated the relationship between HES1, Bmi-1, ALDH1A1, and ALDH1A3 mRNA expression with clinical outcome in EGFR-mutationepositive NSCLC clinical specimens.9-11 The baseline characteristics of the 64 EGFR-mutationepositive NSCLC patients included in this analysis have been previously reported.9-11 A sig-nificant correlation was found between Bmi-1 and ALDH1A1 (r ¼ 0.52; P ¼ .0060), as well as between Bmi-1 and HES1 (r ¼ 0.56; P ¼ .0012). Firstly, HES1, Bmi-1, ALDH1A1, and ALDH1A3 were assessed as continuous variables and then as binary (high vs. low) variables. As continuous variables, HES1, Bmi-1, and ALDH1A1 were independent predictors of PFS benefit, while for OS, the evidence was equivocal, and only Bmi-1 mRNA expression remained significant (Table 1). 
    Discussion
    Previous studies have shown that in lung cancer, CSCs are responsible for aggressive disease behavior and resistance to ther-apy.14-17 This distinct population of tumor 2255-14-3 is capable of continuous self-renewal and differentiation through several signaling pathways, including NOTCH, Hedgehog, and Wnt.18 STAT3, integrin/focal adhesion kinase, and Src help cancer cells in main-taining stem cell properties.10,19 Therefore, first the identification of CSC-specific markers, and second, the development of targeted therapeutics for CSCs elimination, remain a significant challenge. In the present study, we reconfirmed that in 2 EGFR-mutatione positive cell lines, first-, second-, and third-generation EGFR TKIs induce STAT3 phosphorylation,9,10 and increase the fraction of preexisting ALDHþ cells and the expression of CSCs markers. We also show that acquired resistance to osimertinib is related with a
    CSC phenotype. The same EGFR pathway promotes acquisition of stem cell properties in head and neck squamous-cell carcinoma,20,21
    while EGFR blockade enriches and selects for CSCs in EGFR-mutationepositive cells.6,10,22 A correlation between ALDHþ cells and STAT3 activation has also been reported in pancreatic cells.23,24
    Pharmacologic inhibition of STAT3 decreases the number and the size of lung CSCs.23 In the present work we have not explored the effect of silencing CSC markers on sensitivity to EGFR TKIs. However, there is previous evidence that the knockdown of CSCs augments the sensitivity to cancer therapeutics, including EGFR
    Cancer Stem Cell Biomarkers
    A
    free survival 0.75
    -Progression
    Patients at Risk
    Time (months)
    C
    free survival 0.75
    -Progression
    Time (months)
    Patients at Risk
    B
    Overall
    Time (months)
    Patients at Risk
    D
    survival
    Overall
    Patients at Risk
    Time (months)
    Abbreviations: ALDH ¼ aldehyde dehydrogenase; Bmi-1 ¼ B-cellespecific Moloney murine leukemia virus integration site 1; CI ¼ confidence interval; EGFR ¼ epidermal growth factor receptor; mRNA ¼ messenger RNA; NSCLC ¼ nonesmall-cell lung cancer; OS ¼ overall survival; PFS ¼ progression-free survival.
    TKIs. Increased side-population and self-renewal capabilities were reported in gefitinib-resistant cells.4 Oct-4 has been also related to resistance to gefitinib in cell lines and samples of patients.25 Sphere PC9 cells with expression of CSC markers, like CD133, CD44, Oct-4, and ABCG2, were resistant to erlotinib compared to parental cells, with no sphere phenotype.26 Finally, resistance to the second-generation EGFR TKI afatinib has been related with a CSC phenotype, including increased expression of ALDH1.27
    We found that combined EGFR, STAT3, and Src inhibition may overcome the deleterious effect of single EGFR inhibition. In the PC9 cell line, we previously found that the triple com-bination of gefitinib, TPCA-1, and saracatinib is highly 
    synergistic,9 but now we see that it cannot eliminate the ALDHþ cells. In contrast, in the H1975 model, osimertinib, with a STAT3 and/or Src inhibitor, efficiently decreased the osimertinib-induced ALDHþ cells. Our model is depicted in Figure 6. Several markers have been described as identifiers of human lung CSCs, such as CD133,28 ALDH1A1,29 and ALDH1A3.14 ALDH activity is dependent on NOTCH signaling.6,29 The EMT-inducing transcription factor Bmi-1 is also involved in initiation and maintenance of CSCs.30 In breast cancer, Bmi-1 is related with resistance to tamoxifen and down-regulates immune surveillance.31 It also attenuates DNA damageeinduced G2/M checkpoint activation.32 Consistent
    Jordi Codony-Servat et al
    -freesurvival
    Progression 0.50
    Patients at Risk