Alectinib Resistance in ALK-Rearranged Lung Cancer by Dual Salvage Signaling in a Clinically Paired Resistance Model

Tsuji, Takahiro; Ozasa, Hiroaki; Aoki, Wataru; Aburaya, Shunsuke; Funazo, Tomoko; Furugaki, Koh; Yoshimura, Yasushi; Ajimizu, Hitomi; Okutani, Ryoko; Yasuda, Yuto; Nomizo, Takashi; Uemasu, Kiyoshi; Hasegawa, Kôichi; Yoshida, Hironori; Yagi, Yosuke; Nagai, Hiroki; Sakamori, Yuichi; Hirai, Toyohiro; Kim, Young Hak

doi:10.1158/1541-7786.mcr-18-0325

Cited by 39 publications

(28 citation statements)

References 37 publications

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“…Both the KB-C2 and H460/MX20 cells cultured with the AKT inhibitor GSK did not exhibit MDR reversal. In addition to the dominant functions of P110α or P110β in regulating ABC transporters in these cells, AKT may play a separate role in enhancing drug resistance via other functions, such as inducing antiapoptosis or stimulating cell proliferation [50]. Mechanisms relevant to this dual function of P110α or P110β as specific targets for reversing cancer MDR are proposed as illustrated in Fig.…”

Section: Discussionmentioning

confidence: 99%

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

Zhang

Wang

et al. 2020

Mol Cancer

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Background: PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment. Methods: The effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP. Results: By inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb, the ATP-binding cassette transporters P-gp/ ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently. Conclusions: The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.

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Section: Discussionmentioning

confidence: 99%

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

Zhang

Wang

et al. 2020

Mol Cancer

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“…The discovery of anaplastic lymphoma kinase (ALK)-rearranged lung cancer and the development of the first-line targeted inhibitor alectinib (ALC) have resulted in a markedly higher number of patients achieving more than 2 years of progression-free survival (PFS) 3–7 . Despite the promising clinical efficacy of ALC, a cure is generally not achieved, and tumors eventually relapse with resistance 8–11 . Since ALK-rearranged lung cancer may occur in youth 12,13 , the development of curative treatment is an urgent issue.…”

Section: Introductionmentioning

confidence: 99%

“…Secondary mutations in the kinase domain of ALK, such as G1202R, V1180L, and I1171N/S/T, decrease the affinity of ALC to ALK and confer ALC resistance, and further resistance has recently been reported in patients treated with lorlatinib or ceritinib, which are temporally effective for ALC resistance due to secondary mutations 8,17 . Moreover, intra-tumor heterogeneity increases in the later phase of therapy, and resistance mechanisms within a tumor also become more diversified, including several bypass signaling pathways and heterogeneous secondary mutations 8,11 , which may be an obstacle to achieving complete remission. The eradication of tumors in the initial phase of treatment, before the tumor develops complex heterogeneous acquired resistance, is a hypothetical strategy to cure ALK-rearranged cancer.…”

Section: Introductionmentioning

confidence: 99%

YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation

et al. 2020

Self Cite

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Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.

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“…In spite of its effectiveness and initial benefit, drug resistance soon develops due to its toxicity effects. 29 Of note, brain metastases are a characteristic of NSCLC that has been difficult to treat even with F1174L mutation of ALK protein. Thus, fragmentbased drug designing in combination with molecular docking, ADMET analysis and interaction profiling revealed LF16 as a possible hit.…”

Section: Discussionmentioning

confidence: 99%

Design of ALK Inhibitors for Non-Small Cell Lung Cancer – A Fragment Based Approach

Jain

James²,

Shanthi³

et al. 2019

IJPER

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Background: The increasing cases of non-small cell lung cancer pose a relentless threat to human health. Therefore, using fragment-based drug discovery as the modus operandi, the present study aimed to design small molecule inhibitors for Anaplastic Lymphoma Kinase (ALK) positive Non-Small Cell Lung Cancer (NSCLC) and for its secondary mutation (F1174L). Materials and methods: A total of 12 ALK inhibitors (both FDA and clinical) reported in the literature was utilised in the present study to design the novel and potent ALK inhibitors. Fragment script and BREED of Schrödinger suite was used to generate novel structural combinations. GLIDE algorithm was employed to identify the fragments with high binding affinity to the native and mutant forms of ALK. Screened out fragments were subjected to ADMET analysis. Additionally, the impact of F1174L mutation in the stability of ALK protein was assessed using SDM and I-Mutant tools. RING algorithm was employed to compare the pattern of intramolecular interaction between the native and F1174L ALK protein. Results: A novel hybrid molecule LF16 was identified with better binding, superior CNS activity, higher drug score and low toxicity. Annihilation of intramolecular interactions with Ile 1179, Ile 1170 and Phe1098 were found to be the cause of the destabilizing effect of the mutant protein. Of note, these residues were found to play important roles in the formation of F-core as well as in stabilizing αC-helix, which is important for maintaining the inactive form of ALK. Moreover, Conclusion: We believe that these results could foster the designing and development of novel ALK inhibitors towards the management of crizotinib resistance in the near future.

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Alectinib Resistance in ALK-Rearranged Lung Cancer by Dual Salvage Signaling in a Clinically Paired Resistance Model

Cited by 39 publications

References 37 publications

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation

Design of ALK Inhibitors for Non-Small Cell Lung Cancer – A Fragment Based Approach

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