Activation of insulin‐like growth factor‐1 receptor confers acquired resistance to osimertinib in non‐small cell lung cancer with EGFR T790M mutation

Abstract

BackgroundOsimertinib (AZD9291) is a third‐generation EGFR‐tyrosine kinase inhibitor (TKI) that selectively inhibits the activating EGFR mutation and T790M mutation, and is currently used globally to treat EGFR‐mutant non‐small cell lung cancer (NSCLC). However, acquired resistance to osimertinib is inevitable.MethodsWe established osimertinib‐resistant cells (PC9/T790M/AZDR and H1975/AZDR) derived from EGFR‐mutant NSCLC cells harboring T790M mutation, and investigated the mechanism of acquired resistance to osimertinib by whole‐exome sequencing and multiple phospho‐receptor tyrosine kinase (RTK) array. A tumor specimen from an EGFR‐mutant NSCLC patient with acquired resistance to osimertinib was also subjected to immunohistochemical analysis.ResultsWhole‐exome sequencing analysis demonstrated that genetic alterations, such as acquisition of EGFR C797S, loss of T790M mutation, MET amplification, or mutated KRAS, MEK, BRAF, PIK3CA, were not detected. Analysis of phospho‐RTK array revealed that insulin‐like growth factor‐1 receptor (IGF1R) was activated in PC9/T790M/AZDR and H1975/AZDR cells. Knockdown of IGF1R by siRNA as well as inhibition of IGF1R activation by linstinib (IGF1R inhibitor) significantly restored the sensitivity to osimertinib. Immunohistochemical analysis revealed that the expression level of phosphorylated IGF1R was higher in the tumor specimen from the EGFR‐mutant NSCLC patient with acquired resistance to osimertinib than in the specimen collected prior to the treatment.ConclusionsIGF1R activation could occur following treatment with osimertinib in EGFR‐mutant NSCLC with T790M mutation, and might be one of the mechanisms underlying osimertinib resistance. Combined treatment of osimertinib and IGF1R inhibitor might be effective in overcoming the acquired resistance to osimertinib induced by IGF1R activation.Key points Significant findings of the study: Using osimertinib‐resistant cells, we found that IGF1R activation induced by osimertinib treatment in EGFR‐mutant NSCLC with T790M mutation is involved in resistance. Increased phosphorylation of IGF1R was observed in the tumor specimen from an EGFR‐mutant NSCLC patient with acquired osimertinib resistance. What this study adds: IGF1R activation might be one of the mechanisms of osimertinib resistance. A combination therapy with osimertinib and an IGF1R inhibitor might be an optimal approach for overcoming the acquired resistance to osimertinib induced by IGF1R activation.

CDK4/6 inhibitor palbociclib overcomes acquired resistance to third‐generation EGFR inhibitor osimertinib in non‐small cell lung cancer (NSCLC)

“…A series of studies have been published on acquired resistance to osimertinib. [24][25][26][27][28][29][30] The L858R mutation combined with T790M mutation was found to be more similar in real-world patients who acquired T790M mutation after firstor second-generation TKIs. 10,11 In this study, common osimertinib resistance mechanisms, such as C797X, loss of T790M, amplification of MET, and the mutation of KRAS, BRAF, MEK and PI3K, were not found in H1975OR cells, 23,30 which is similar to previous studies 13 and represents a more common clinical situation.…”

“…25,29 Shah et al found that for H1975, osimertinib and rociletinib were used to induce drug resistance, respectively, and secondary TPX2 overactivation caused the increase of AURKA phosphorylation and BIM phosphorylation, which led to BIM ubiquitin degradation unable to play its role in inducing apoptosis. 25,29 AURKA inhibitor MLN8237 could block the phosphorylation of BIM, and BIM could induce apoptosis again to reverse the drug resistance of TKI of the third-generation osimertinib. Aurora kinase inhibitors were found to suppress this adaptive survival program, thereby increasing the magnitude and duration of EGFR inhibitor response in preclinical models.…”

“…29 Hayakawa et al showed that the activation of IGF1R was involved in the acquired resistance of osimertinib. 25 Both the knockdown IGF1R and IGF1R inhibitor could reverse the drug resistance and reconstruct the sensitivity of osimertinib. 24,25 In this study, there was no detection of AURKA kinase and IGF1R, so it is impossible to determine whether there was overactivation of AURKA and IGF1R.…”

Development of Liposomal Vesicles for Osimertinib Delivery to EGFR Mutation—Positive Lung Cancer Cells

“…Considering the physicochemical properties and biological activity, we have found egg-PC liposomes as the most promising formulation for further development. Therefore, we additionally tested the cytotoxicity of 1-OSI, 1-NL formulations, and free OSI in other NSCLC, PC-9 cell line with a deletion in exon 19 of the EGFR gene which is sensitive to OSI [ 61 ], and A549 line with wild type EGFR gene which is known to be resistant to OSI treatment [ 62 ]. As shown in Figure 7 E,F, cytotoxicity profiles determined for OSI and its liposomal form (IC 50 at ca.…”

The value of local consolidative therapy in Osimertinib-treated non-small cell lung cancer with oligo-residual disease

“…It is well known that Osimertinib has higher potency against both cranial and extracranial tumor lesions, when compared with rst-or second-generation EGFR TKIs. However, acquired resistance to Osimertinib was also inevitable [20,21], and the clinical values of LCT in the era of Osimertinib for EGFR-mutant NSCLC remained unknown.…”