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Aspirin (acetylsalicylic acid) is a classic anticoagulant that has become one of the most commonly used medications. A large body of evidence has demonstrated its potential for anticancer effects, particularly in PIK3CA-mutated colorectal cancer. Recent studies have shown that aspirin sensitizes osimertinib and that patients with EGFR-mutant non-small cell lung cancer (NSCLC) who take aspirin and osimertinib are more likely to have better survival.
Recently, a research team from the Department of Respiratory Medicine of Daping Hospital of the Army Medical University found that PIK3CG and PIK3CA mutations can induce osimertinib resistance, and can be effectively reversed by aspirin in vitro and in vivo.
Figure 1: Screenshot of the homepage of the study
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Take aspirin daily to reverse osimertinib resistance
The research team previously reported that a patient who was resistant to osimertinib unfortunately suffered from unstable angina pectoris during treatment, so the combination of 100mg of aspirin and osimertinib per day unexpectedly effectively reversed osimertinib resistance. Subsequently, tumor biopsies revealed multiple mutations, including EGFR L858R, T790M, TP53, and PIK3CG L468M. Based on these results, it is hypothesized that the acquired PIK3CG L468M mutation may lead to osimertinib resistance.
Figure 1.Schematic diagram of the treatment patients received and the genetic alterations detected at each time point.
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Aspirin re-sensitizes to osimertinib
The research team further investigated whether aspirin re-sensitizes drug-resistant cells to osimertinib. Aspirin at 25 and 200 μmol/L was confirmed to slightly reduce the viability of PIK3CG or PIK3CA mutant Ba/F3 and NSCLC cell lines, respectively. Therefore, osimertinib-resistant cells PIK3CG and PIK3CA mutant Ba/F3-EGFR Del19 and Ba/F3-EGFR Del19-T790M cells were simultaneously treated with osimertinib and aspirin (25 μmol/L). Strikingly, these osimertinib-resistant cells can be re-sensitized to osimertinib by aspirin. Similar results were observed in PIK3CG and PIK3CA mutant NSCLC cell lines, which can be effectively reversed with 200 μmol/L aspirin treatment.
In order to further evaluate the molecular mechanism of aspirin regulating osimertinib resistance, the expression of PI3K/Akt/mTOR pathway was explored. Aspirin was found to significantly reduce the expression of PI3K (p110γ) and PI3K (p110α) and inhibit the Akt/mTOR pathway. At the same time, similar results were observed in NSCLC cells (Figure 3D). Overall, these results suggest that aspirin can reverse PIK3CG and PIK3CA mutation-induced osimertinib resistance through a PI3K inhibitory-dependent mechanism.
Figure 2. (A) Effect of different doses of aspirin on various PI3KCG and PI3KCA mutant cell lines.
(B) Cell viability was analyzed by CCK-8 assay.
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Aspirin + osimertinib enhances antitumor activity
In addition, the research team also found that osimertinib (10mg/kg) and aspirin (20mg/kg) had a synergistic effect when co-administered, significantly reducing tumor size in a mouse model of CDX. After 4 weeks of administration, the combination resulted in a significant reduction in tumor volume compared to the other three treatment groups (control, osimertinib alone, and aspirin alone). IHC staining showed that the expression of PI3K (p110γ) and Ki67 in the combination treatment group was significantly reduced, indicating that the combination of aspirin and osimertinib significantly inhibited cell proliferation. In addition, the combination of aspirin and osimertinib was further observed to inhibit the expression of PI3K (p110γ) and the Akt/mTOR signaling pathway in PIK3CG-mutant CDX tumors. Taken together, these results suggest that the therapeutic benefits associated with the combination of aspirin and osimertinib apply to PIK3CG (L468M) mutations in vivo.
Figure 3.(A) Tumor changes at 4 weeks post-dose.
(B and C) Tumor weight (g) and volume (mm3) treated with osimertinib, aspirin, and combination therapy.
(C) Nude mouse body weight is measured after the indicated treatment, and the data is shown as mean ± SEM (n=3).
Summary
Overall, aspirin has been found to reverse osimertinib resistance caused by PIK3CG and PIK3CA mutations. In addition, aspirin combination therapy also has the characteristics of few side effects and low cost, and can play a role at low concentrations, which is worthy of wide clinical application.
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Bibliography:
[1] Han, Rui et al. “The potential therapeutic regimen for overcoming resistance to osimertinib due to rare mutations in NSCLC.” iScience vol. 26,7 107105. 12 Jun. 2023, doi:10.1016/j.isci.2023.107105
Source of this article: Treasure Book of Finding Medicine
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