Anaplastic lymphoma kinase inhibitors in elderly patients with advanced non-small cell lung cancer

Zaarour, Mazen; Nazha, Bassel; Weerasinghe, Chanudi; Moussaly, Elias; Terjanian, Terenig

doi:10.1080/14737140.2016.1204235

Cited by 2 publications

(4 citation statements)

References 33 publications

(23 reference statements)

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“…difference in age could be a notable finding due to either a generalization of ALK-mutant gene assessment or changes related to the aging of the population in developed countries. In addition, there have been few reports with regards to the treatment of elderly ALK-rearranged NSCLC patients (17)(18)(19). Therefore, we conducted this study to clarify characteristics of elderly ALK-rearranged NSCLC patients in in real clinical practice.…”

Section: Discussionmentioning

confidence: 99%

“…ALK rearranged gene mutation is an oncogenic driver of NSCLC and commonly associated with younger age (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Although under a small number, however, elderly ALKrearranged NSCLC patients also have been reported (17)(18)(19). There exist few reports on the characteristics of these elderly patients (17)(18)(19).…”

mentioning

confidence: 99%

“…Although under a small number, however, elderly ALKrearranged NSCLC patients also have been reported (17)(18)(19). There exist few reports on the characteristics of these elderly patients (17)(18)(19). Recently, we performed a retrospective study in real clinical practice of 129 ALK-rearranged NSCLC patients.…”

mentioning

confidence: 99%

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Clinicopathological Features in Elderly ALK-rearranged Non-small Cell Lung Cancer Patients

Miyazaki¹,

Sato²,

Kodama³

et al. 2020

In Vivo

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Aim: To clarify the clinicopathological features in elderly anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) patients. Patients and Methods: A retrospective study was performed in 129 ALK rearranged NSCLC patients diagnosed between April 2008 and March 2019 in fifteen Institutions of the Ibaraki prefecture, Japan. Results: Median age of patients was 63 years. In 59 patients aged 65 and older, the proportions of patients with advanced stage and those treated with ALKtyrosine kinase inhibitor (TKI) were lower than those younger than 65 years. There was no difference in overall survival (OS) between the two age groups. Among the elderly patients, no difference was observed in OS between the patients aged 65-69 and those aged 70 and older. In 89 patients treated with TKI, no significant differences were observed in the progression-free survival of TKIs and OS between patients aged 65 and older and those younger than 65, respectively. Conclusion: Evaluation of ALK gene status and TKI treatment are desirable even for elderly patients. Advances in molecular biology have led to discovery of specific driver genes in certain cancer types and therefore to development of specific therapeutics (1, 2). This new trend is evident in the clinical practice of NSCLC patients. Mutations in the anaplastic lymphoma kinase (ALK) fusion gene is one such driver gene. Long-term survival can be expected in ALKrearranged NSCLC patients, but its frequency is very rare (1, 2001 This article is freely accessible online.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Clinicopathological Features in Elderly ALK-rearranged Non-small Cell Lung Cancer Patients

Miyazaki¹,

Sato²,

Kodama³

et al. 2020

In Vivo

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“…Several selective ALK inhibitors have been FDA approved for use in patients whose tumors display evidence of increased ALK activity 32 . The selective nature of such ALK inhibitors is associated with greater tolerability due to limited off-target effects 33 . ALK positivity, as assessed by immunohistochemistry (IHC), is present in 20.9% and 36% of ovarian and breast cancers, respectively, and more prevalent in aggressive histological subtypes, such as high-grade serous ovarian cancer (HGSOC) (28% in HGSCO versus 0% in other ovarian cancer subtypes, P = 0.002) and triple-negative breast cancer (TNBC) (47% in TNBC versus 34% in non-TNBC, P = 0.0034) 30 , 31 .…”

Section: Mainmentioning

confidence: 99%

Targeting the ALK–CDK9-Tyr19 kinase cascade sensitizes ovarian and breast tumors to PARP inhibition via destabilization of the P-TEFb complex

et al. 2022

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Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor growth and improve survival of mice in PARP inhibitor-/platinum-resistant tumor xenograft models. Using human tumor biospecimens, we further demonstrate that phosphorylated ALK (p-ALK) expression is associated with resistance to PARP inhibitors and positively correlated with p-Tyr19-CDK9 expression. Together, our findings support a biomarker-driven, combinatorial treatment strategy involving ALK and PARP inhibitors to induce synthetic lethality in PARP inhibitor-/platinum-resistant tumors with high p-ALK–p-Tyr19-CDK9 expression.

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Anaplastic lymphoma kinase inhibitors in elderly patients with advanced non-small cell lung cancer

Cited by 2 publications

References 33 publications

Clinicopathological Features in Elderly ALK-rearranged Non-small Cell Lung Cancer Patients

Clinicopathological Features in Elderly ALK-rearranged Non-small Cell Lung Cancer Patients

Targeting the ALK–CDK9-Tyr19 kinase cascade sensitizes ovarian and breast tumors to PARP inhibition via destabilization of the P-TEFb complex

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