Here, we demonstrate that neuroblastoma cells overcome the interference of tumor suppressor p16<sup>INK4a</sup> in cell proliferation, which is due to its latent interaction with CDK4 and CDK6.
Expression of CDK4 was positively associated with plasma PTH level (r = 0.60, p = 0.04) and tumor weight (r = 0.80, p = 0.02) of the adenoma patients, respectively.
These data indicate that the combination of cytotoxic and cytostatic agents could represent an important modality in those tumor types that are relatively resistant to CDK4/6 inhibitors.
Tumor biopsy with genomic sequencing and repeat biomarker analysis in patients with CDK4/6i- and endocrine-resistant disease will be integral to guide subsequent treatment strategies and to inform clinical trial eligibility.
NF1 loss promoted ER-independent cyclin D1 expression, which could be therapeutically targeted with CDK4/6 inhibitors <i>in vitro</i> Patients with <i>NF1</i> mutations detected in baseline circulating tumour DNA had a good outcome on the CDK4/6 inhibitor palbociclib and fulvestrant.
Compared with the well-known CDK4/6 inhibitor palbociclib, orally administered SHR6390 led to equivalent or improved tumor efficacy against a panel of carcinoma xenografts, and produced marked tumor regression in some models, in association with sustained target inhibition in tumor tissues.
On the one hand, CDK4 phosphorylated the tumor suppressor folliculin (FLCN), regulating mTORC1 recruitment to the lysosomal surface in response to amino acids.
Besides the identification of well-recognized driver mutations of <i>BRAF</i> (3.1%), <i>RAS</i> family (6.2%), <i>NF1</i> (7.8%), and <i>KIT</i> (23.1%) in MMs, our study also found that (i) mutations and amplifications in the transmembrane nucleoporin gene <i>POM121</i> (30.8%) defined a patient subgroup with higher tumor proliferation rates; (ii) enrichment of structural variations between chromosomes 5 and 12 defined a patient subgroup with significantly worse clinical outcomes; (iii) over 50% of the MM patients harbored recurrent focal amplification of several oncogenes (<i>CDK4, MDM2,</i> and <i>AGAP2</i>) at 12q13-15, and this co-occurred significantly with amplification of <i>TERT</i> at 5p15, which was verified in the validation cohort; (iv) the PDX trial demonstrated robust antitumor effects of palbociclib in MMs harboring <i>CDK4</i> amplification.
The CDK4/6 inhibitor palbociclib reduces tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition.
SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16<sup>INK4a</sup>-deficient profile associated with positive responses to CDK4/6 inhibitors.
In C33A xenografts, Ribociclib inhibited tumor growth associated with decreased expressions of CDK4, CDK6, cyclin D1, Rb and Ki-67, and also significantly increased tumor cell apoptosis.
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation.
Novel therapeutic strategy with combination of a selective CDK4/6 inhibitor palbociclib (PAL) with a tyrosine kinase inhibitor (TKI) sorafenib (SOR) is reported to impair tumour growth and significantly increased survival in various preclinical models of HCC.
Consistent with circadian regulation, a CDK4/6 inhibitor approved for cancer treatment reduced growth of cultured cells and mouse tumors in a time-of-day-specific manner.
The micro-SPECT/CT study showed that complex <sup>99m</sup>Tc-<b>L4</b> had visible uptake at the tumor site, and the accumulation was clearly reduced in the image after pretreatment with palbociclib, further indicating CDK4/6 specificity.
Of additional importance, this combined treatment has potent efficacy in ESCC cells with acquired resistance to CDK4/6 inhibitors in vitro and in xenograft tumors.