Acquired resistance to an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in an uncommon G719S EGFR mutation

Abstract

Background Acquired resistance (AR) to an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is a common event, and several underlying mechanisms, including T790 M, MET amplification and PTEN downregulation, have been reported for the common EGFR mutations. EGFR G719X is an uncommon mutation that has been reported to show sensitivity to EGFR-TKIs. However, no established cell lines harboring the EGFR G719X have been reported in the literature. Materials and Methods G719S-GR cells were established from malignant pleural effusion of a patient whose tumor developed AR from gefitinib treatment. G719S-GR cells were then genotyped and tested for drug sensitivities. Multiplex ligation-dependent probe amplification (MLPA) was used to compare the clinical tumor samples with G719S-GR. Results G719S-GR cells were resistant to EGFR-TKIs with an LC50 of around 10 μM. A genomic analysis showed that G719S-GR cells harbor the EGFR G719S mutation as well as the amplification of EGFR locus. The homozygous deletion of CDKN2A and the loss of PTEN and TSC1 were also detected. On comparing the copy number of tumor suppressor genes using MLPA, G719S-GR cells were found to lack one copy of PTEN, which was not observed in a tumor obtained before gefitinib treatment. Loss of PTEN may result in AKT activation. The mTORC1/2 inhibitor Torin-1 was able to inhibit the downstream signaling when combined with osimertinib. Discussion The newly established G719S-GR cell line may be useful for investigating the mechanism underlying the development of AR in the G719X mutation; the loss of PTEN may be one such mechanism.

Afatinib treatment response in advanced lung adenocarcinomas harboring uncommon mutations

“… 34 However, the mechanism of acquired resistance for uncommon mutations remains unclear. 35 , 36 A multicenter study has shown that acquired T790M mutation was common in patients with NSCLC with icotinib‐resistant EGFR uncommon mutations. Other several resistance mechanisms to icotinib in NSCLC harboring uncommon mutations include EGFR extracellular domain mutation, BCL2L11 loss, MET amplification, ERBB2 amplification, MYC amplification, PTEN mutation, and PIK3CA mutation.…”

Deep Next Generation Sequencing Identifies Somatic Mutational Signature in Egyptian Colorectal Cancer Patients

“…The frequency of those mutations increased from the colitis to nally the CRC, so they could be used as predictors for disease progression. Most of the above identi ed somatic mutations were observed mostly with the CRC [47], except for (c.640delT in ATM), (c.1621A > C in KIT), (c.2071G > A in RET) & (c.121delG in TP53) which were observed respectively in breast [57], soft tissues [58] & head and neck cancers [59]. This is the rst study to report their association with the colorectal carcinogenesis in Egyptian CRC patients.…”

A rotamer relay information system in the epidermal growth factor receptor–drug complexes reveals clues to new paradigm in protein conformational change

“…Indeed, simulations indicate that the distance between residues L718 and G796 is increased widening the ATP-binding site for TKIs to enter (conversely, the T790M mutation causes the distance between L718 and G796 to decrease) [60] . Moreover, the G719S mutation destabilizes the inactive conformation and promotes the active conformation of the kinase, leading to more TKI sensitivity [61] , [62] , [63] , [64] , [65] . However, when G719S is combined with T790M as a double mutation, the secondary T790M mutation overturns the impact of G719S on the distance between the P-loop and activation loop [60] .…”