ALK L1152P lies within the protein kinase domain of the Alk protein (UniProt.org). L1152P has been demonstrated to confer drug resistance in the context of ALK rearrangement in culture (PMID: 24675041), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Apr 2024).

Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified as potent oncogenic drivers in several malignancies, including non-small cell lung cancer (NSCLC). The discovery of ALK inhibition using a tyrosine kinase inhibitor (TKI) has dramatically improved the outcomes of patients with ALK-mutated NSCLC.

2023年9月29日 · ALK fusions/rearrangements are discerned in >50% of inflammatory myofibroblastic tumors (IMTs) and anaplastic large cell lymphomas (ALCLs), but only in ~0.2% of other cancers outside of non-small...

This steric obstruction leads to a loss in potency as reflected by the shift in IC50 values observed for ceritinib and crizotinib. In contrast to the G1202R mutation, the T1151 insertion, L1152P, C1156Y, and F1174C inhibitor resistant mutants all map to the N-terminal lobe of the ALK catalytic domain and flank opposing ends of the αC-helix.

2018年7月13日 · The maximum of ΔΔG FR predicted occurred at the mutation energy of the inhibitor ceritinib against the single-point mutation L1152P, indicating that ceritinib bound to the mutation much less closely than to the wild-type ALK and strong drug resistance may occur.

2022年6月15日 · Crizotinib, a first generation ALK inhibitor, is widely prescribed for ALK-positive NSCLC in clinic. Resistance to crizotinib and other ALK inhibitors has been problematic. Addressing resistance, here we describe discovery and development of a novel, proprietary spirocyclic diamine-substituted aryl phosphine oxide series of inhibitors, which ...

In a preclinical study, transformed cells expressing ALK L1152P in the context of EML4-ALK demonstrated reduced sensitivity to Zykadia (ceritinib) compared to cells expressing EML4-ALK in culture (PMID: 27780853).

2020年4月16日 · 研究进一步基于ngs的基因分析共检测到16例患者在克唑替尼/化疗治疗后发生了继发性alk基因突变（包括：g1202r、l1152p、g1269a、l1196m等位点突变），其中有11例alk继发突变患者继续接受了阿来替尼治疗，整体orr达到了55%，化疗组为0%。

TPX-0131 demonstrates superior dose-dependent anti-tumor efects in Ba/F3 cell-derived xenograft tumors with EML4-ALK G1202R, EML4-ALK G1202R/L1198F, or EML4-ALK G1202R/L1196M fusions relative to lorlatinib. TPX-0131 inhibited EML4-ALK G1202R/L1196M phosphorylation in vivo (Figure 3)

In this Review, we discuss the molecular underpinnings of acquired resistance to ALK-directed therapy and highlight new treatment approaches aimed at inducing long-term remission in ALK+ disease. Over the past few decades, advances in lung cancer diagnostics and treatments have transformed patient outcomes1,2.