Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • br Discussion To our knowledge

    2022-11-18


    Discussion To our knowledge, this is the first case report that demonstrates the presence of a novel T1151K ALK mutation in a patient with disease progression after crizotinib and then ceritinib. As early as 2011, Zhang et al. identified T1151K among other resistance mutations to crizotinib in Ba/F3 cells through an accelerated mutagenesis screen [4]. ALK T1151M, the substitution of threonine with methionine instead of lysine, was identified in patients with neuroblastoma in 2014 [5]. Recently, Amin et al. reported the emergence of T1151M in a nucleophosmin (NPM)-ALK+ anaplastic large-cell lymphoma cell line (DHL-1) grown in ceritinib [6]. Another mutation T1151ins, an amino SKL2001 australia insertion, has been shown in ALK+ NSCLC patients progressing on crizotinib [7]. Of note, molecular analysis was not performed on our patient prior to ceritinib therapy, so it is unclear when the T1151K mutation developed in relation to crizotinib and ceritinib exposure. Since he experienced rapid disease progression while on crizotinib and his response to ceritinib was stable disease at best, it is reasonable to speculate that this mutation emerged after crizotinib but prior to ceritinib therapy. In order to decipher how T1151K relates to differential sensitivity to ALK inhibition, co-crystal structures of TKI/ALK are displayed here (Fig. 1). Ceritinib (Fig. 1A) has a strong interaction with the P-loop reflected by well-ordered β1 and β2 sheets in contrast to alectinib (Fig. 1B) and lorlatinib (Fig. 1C). The P-loop is well organized to facilitate a strong interaction between V1130 on the β2 sheet and the phenyl group of ceritinib (Fig. 1D). The carboxyl group of E1129 forms hydrogen bond with G1123 on the β1 sheet, a feature not present in the alectinib/ALK or lorlatinib/ALK co-crystal structure. In addition, H1124, E1129 and Y1131 form a well-organized sandwich type stacking interaction to help position V1130 (Fig. 1E). All these unique interactions are predicted to be interrupted by the T1151K mutation and its interaction with the carboxyl group of E1129 (Fig. 1E), leading to disorder of the P-loop and weakened association of V1130 with ceritinib. Another possibility is that because T1151 is located near the N-terminus of the ALK catalytic domain, mutations at this residue may cause conformational changes of the kinase resulting in higher affinity for ATP and therefore diminished inhibitor binding [8]. However, the activation of the ALK tyrosine kinase domain (TKD) may not be as strong as other mutations such as I1171 or F1174 based on a computational analysis of neuroblastoma patients with mutated ALK TKDs by Bresler et al.[5]. In contrast to ceritinib, neither alectinib nor lorlatinib has a strong interaction with the P-loop reflected by relatively disordered P-loops shown in the co-crystal structures (Fig. 1B and C respectively). The carboxyl group of E1129 forms hydrogen bond with Y1131 instead of G1123 for both alectinib (Fig. 1F) and lorlatinib (Fig. 1G). Therefore the binding of these two TKIs with ALK may not be impacted by the T1151K mutation. Furthermore, an in vitro assay utilizing an FL5.12 EML4-ALK construct demonstrated that T1151M was sensitive to alectinib based on negative log IC50 fold-change. However, the change of IC50 in response to brigatinib was insignificant suggesting that T1151M was neither sensitive nor resistant to it [6]. Similar to ceritinib, brigatinib also has a strong interaction with the P-loop. Therefore we speculate that brigatinib may not completely overcome the T1151K/M resistant mutations. This case has illustrated the importance of obtaining a repeat tissue biopsy upon disease progression for patients on targeted therapies. If our patient progresses again, we plan to obtain another biopsy to explore mechanisms of resistance among which emergence of secondary ALK mutations is only one of many ways in which tumor cells have adapted to survive. We have recently reported a case of small cell lung cancer transformation in a patient with prior exposure to ceritinib, alectinib, and lorlatinib [9]. Liquid biopsy in this case would have been insufficient to detect this critical histological conversion. Therefore, whenever possible tissue biopsy is always preferred. Secondly, CGP of the biopsied specimen is equally important as it may also allow identification of off-target resistance mechanisms including alterations of bypass signaling pathways, in addition to on-target resistance mutations. Finally, we conclude that the T1151K ALK mutation confers resistance to ceritinib, which may be rescued by alectinib or lorlatinib.