Palbociclib overcomes afatinib resistance in non-small cell lung cancer

Nie, Heng–Yong; Zhou, Xiaoyan; Du, Shouying; Nie, Chunjie; Zhang, Xiaojian; Huang, Jianmin

doi:10.1016/j.biopha.2018.10.170

Cited by 16 publications

(14 citation statements)

References 32 publications

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“…In preclinical cell culture and xenograft models, Nie et al 16 demonstrated that palbociclib combined with the secondgeneration TKI afatinib reversed acquired resistance to afatinib. In a single-institution study of 33 patients with EGFR-mutated NSCLC who were treated with firstgeneration TKIs, 17 78% had at least one concomitant genomic alteration, with the most common being TP53 mutations (30.3%) and CDK4 (24.2%) or CDKN2A (21.2%) copy number alterations.…”

Section: Discussionmentioning

confidence: 99%

Palbociclib in Patients With Non–Small-Cell Lung Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study

Ahn

Mangat

Garrett‐Mayer

et al. 2020

JCO Precision Oncology

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PURPOSE The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a phase II pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results in a cohort of patients with non–small-cell lung cancer (NSCLC) with CDKN2A alterations treated with palbociclib are reported. METHODS Eligible patients were ≥ 18 years old with advanced NSCLC, no remaining standard treatment options, measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Patients with NSCLC with CDKN2A alterations and no Rb mutations received palbociclib 125 mg orally once daily for 21 days, followed by 7 days off. Simon’s two-stage design was used with a primary study end point of objective response or stable disease (SD) of at least 16 weeks in duration. Secondary end points are progression-free survival (PFS), overall survival (OS), and safety. RESULTS Twenty-nine patients were enrolled from January 2017 to June 2018; two patients were not evaluable for response but were included in safety analyses. One patient with partial response and six patients with SD were observed, for a disease control rate of 31% (90% CI, 19% to 40%). Median PFS was 8.1 weeks (95% CI, 7.1 to 16.0 weeks), and median OS was 21.6 weeks (95% CI, 14.1 to 41.1 weeks). Eleven patients had at least 1 grade 3 or 4 adverse event (AE) or serious AE (SAE) possibly related to palbociclib (most common, cytopenias). Other AEs or SAEs possibly related to the treatment included anorexia, fatigue, febrile neutropenia, hypophosphatemia, sepsis, and vomiting. CONCLUSION Palbociclib monotherapy demonstrated evidence of modest antitumor activity in heavily pretreated patients with NSCLC with CDKN2A alterations. Additional investigation is necessary to confirm efficacy and utility of palbociclib in this population.

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Section: Discussionmentioning

confidence: 99%

Palbociclib in Patients With Non–Small-Cell Lung Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study

Ahn

Mangat

Garrett‐Mayer

et al. 2020

JCO Precision Oncology

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“…Rb has been found lost in 100% of NSCLC patients underwent histological transformation to small-cell lung cancer (SCLC) after gefitinib treatment [31], but no data are available on the phosphorylation status of Rb in patients with different mechanisms of resistance to EGFR-TKI. It has been reported that afatinib did not suppress Rb phosphorylation in afatinib-resistant PC9 cells [13], and, very recently, that p-Rb was increased in osimertinibresistant H1975 cells (H1975OR), with an undefined resistance mechanism, in comparison with the parental ones [12].…”

Section: Discussionmentioning

confidence: 99%

“…One study evaluated the effects of palbociclib combined with osimertinib only in one osimertinib-resistant cell model (H1975) with an undefined mechanism of resistance [12]. In another paper, palbociclib was used in combination with afatinib in two afatinib-resistant cell models that were not characterized for the underlying mechanisms of resistance [13].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of the CDK4/6 Dual Inhibitor Abemaciclib in EGFR-Mutated NSCLC Cell Lines with Different Resistance Mechanisms to Osimertinib

Monica

Fumarola

Cretella

et al. 2020

Cancers

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Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or -independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senescence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment.

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“…102) as well as afatinib (2nd generation EGFR inhibitor) (Ref. 103) in vitro . Similarly, combining palbociclib with erlotinib (first-generation EGFR inhibitor) in EGFR -amplified models of oesophageal squamous cell carcinoma was shown to prevent erlotinib resistance in vitro and improve in vivo response to erlotinib in murine models (Ref.…”

Section: Combination Treatment Strategies To Mitigate Resistancementioning

confidence: 99%

Anti-cancer therapy with cyclin-dependent kinase inhibitors: impact and challenges

Reinius

Smyth

2021

Expert Rev. Mol. Med.

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The introduction of cyclin-dependent kinase 4/6 inhibitors (CKIs) has marked a major development in the standard treatment of advanced breast cancer. Extensive preclinical, translational and clinical research efforts into CKI agents are ongoing, and clinical application of this class of systemic anti-cancer therapy is anticipated to expand beyond metastatic breast cancer treatment. Emerging evidence indicates that mechanisms by which CKI agents exert their therapeutic effect transcend their initially expected impacts on cell cycle control into the realms of cancer immunology and metabolism. The recent expansion in our understanding of the multifaceted impact of CKIs on tumour biology has the potential to improve clinical study design, therapeutic strategies and ultimately patient outcomes. This review contextualises the current status of CKI therapy by providing an overview of the original and emerging insights into mechanisms of action and the evidence behind their current routine use in breast cancer management. Recent preclinical and clinical studies into CKIs across tumour types are discussed, including a synthesis of the more than 300 clinical trials of CKI-combination treatments registered as of November 2020. Key challenges and opportunities anticipated in the 2020s are explored, including treatment resistance, combination therapy strategies and potential biomarker development.

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Palbociclib overcomes afatinib resistance in non-small cell lung cancer

Cited by 16 publications

References 32 publications

Palbociclib in Patients With Non–Small-Cell Lung Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study

Palbociclib in Patients With Non–Small-Cell Lung Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study

Efficacy of the CDK4/6 Dual Inhibitor Abemaciclib in EGFR-Mutated NSCLC Cell Lines with Different Resistance Mechanisms to Osimertinib

Anti-cancer therapy with cyclin-dependent kinase inhibitors: impact and challenges

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