Osimertinib resistance
When osimertinib was given as a first-line therapy, MET amplification was the most common resistance mechanism, encountered in 15% of patients by next-generation sequence ctDNA analysis. Moreover, this percentage is expected to be higher in tissue, due to the underestimation of gene amplification in plasma.
The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway 1)
Circular RNAs are involved in EGFR-TKI resistance, while the role of hsa_circ_0005576 in the osimertinib resistance of LUAD remain unknown. In a study, Liu et al. demonstrated that hsa_circ_0005576 could facilitate the osimertinib-resistant LUAD cells. Briefly, knockdown of hsa_circ_0005576 not only suppressed the proliferation and promoted the apoptosis of resistant LUAD cells, but also increased its sensitivity to osimertinib. Mechanistically, hsa_circ_0005576, serving as a miRNA-sponge, could directly interact with miR-512-5p and subsequently upregulate the miR-512-5p-targeted insulin-like growth factor 1 receptor (IGF1R). The rescue assays indicated that miR-512-5p inhibition could reverse the effects of hsa_circ_0005576 knockdown on LUAD cells resistance to osimertinib. Overall, the study revealed that hsa_circ_0005576 regulates proliferation and apoptosis through miR-512-5p/IGF1R signaling, further which contributes to resistance of LUAD cells to osimertinib. Meanwhile, it provides a novel insight on the mechanism underlying osimertinib resistance of LUAD 2).
While surgery is the mainstay of treatment in patients with a sellar mass, optic compression, and visual deficits, those with EGFR-mutated NSCLC-PitM may benefit from early initiation of such systemic therapies, rather than surgical intervention, with good ophthalmologic results 3).
Patients with non-Small-cell lung cancer (NSCLC) initially responding to tyrosine kinase inhibitors (TKIs) eventually develop resistance due to accumulating Epidermal growth factor receptor mutations and additional lesser investigated mechanisms such as the participation of the tumor microenvironment (TME).
Zhu et al. examined the potential for MET inhibitor capmatinib for the treatment of osimertinib-resistant NSCLCs and normalizing the TME.
They first established that HCC827 and H1975 cells showed increased resistance against osimertinib when co-cultured with CAFs isolated from osimertinib-resistant patients. Additionally, they showed that CAFs promoted epithelial-mesenchymal transition (EMT) and self-renewal ability in both HCC827 and H1975 cells. We subsequently found that both CAF-cultured HCC827 and H1975 showed a significantly higher expression of MET, Akt, Snail and IL-1β, which were associated with survival and inflammatory responses. These cells in turn, promoted the generation of CAFs from normal lung fibroblasts. Subsequently, we observed that the treatment of capmatinib resulted in the re-sensitization of CAF-co-cultured H1975 and HCC827 to osimertinib, in association with reduced EMT and self-renewal ability. MET-silencing experiment using siRNA supported the observations made with capmatinib while with a greater magnitude. MET-silenced cell exhibited a severely hindered expression of inflammatory markers, IL-1β and NF-κB; EMT markers, Snail and Vimentin, while increased E-cadherin. Finally, we demonstrated that the combination of capmatinib and osimertinib led to an increased tumor inhibition and significantly lower number of CAFs within the patient derived xenograft (PDX) model.
Taken together, the findings suggested that an increased MET/Akt/Snail signaling was induced between the NSCLC cells and their TME (CAFs), resulting in osimertinib resistance. Suppression of this pathway by capmatinib may bypass the EGFR activating mutation and overcomes osimertinib resistance by targeting both tumor cells and CAFs 4).