Coadministration of Trametinib and Palbociclib Radiosensitizes KRAS-Mutant Non–Small Cell Lung Cancers In Vitro and In Vivo

Abstract

Purpose: To investigate the potential roles that p16 (CDKN2A) and RB activation have in sensitization to MEK inhibitor in resistant KRAS-mutant non-small cell lung cancer cells (NSCLC) in vitro and in vivo.Experimental Design: Cell viability was measured with MTS assays. Effects of administration of radiation and combination drug treatments were evaluated by clonogenic assay, flow cytometry, and Western blots. DNA repair was assessed using immunofluorescent analysis. Finally, lung cancer xenografts were used to examine in vivo effects of drug treatment and radiation therapy.Results: In this study, we showed that sensitivity to MEK inhibitor correlated to the RB/p16/CDK4 pathway and knockdown of RB induced resistance in cell lines sensitive to MEK inhibitor. Also, overexpression of p16 and inhibition of CDK4 had the ability to sensitize normally resistant cell lines. Our data indicated that the MEK inhibitor (trametinib, GSK112012) cooperated with the CDK4/6 inhibitor (palbociclib, PD0332991) to strongly reduce cell viability of KRAS-mutant NSCLCs that were resistant to the MEK inhibitor in vitro and in vivo. In addition, we report for the first time that resistance of KRAS-mutant NSCLCs to MEK inhibitor is, at least partly, due to p16 mutation status, and we described a drug combination that efficiently reactivates the RB tumor suppressor pathway to trigger radiosensitizing effects, apoptosis, and cell-cycle arrest.Conclusions: Our findings suggest that MEK inhibitor in combination with CDK4/6 inhibitor has significant anti-KRASmutant NSCLC activity and radiosensitizing effect in preclinical models, potentially providing a novel therapeutic strategy for patients with advanced KRAS-mutant NSCLCs.

Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth

“…Delayed DNA double-strand break repair has recently been reported for irradiated KRASmutant non -small cell lung cancers that are cotreated with palbociclib and the MEK inhibitor trametinib. 28 Our findings, as well as the findings of others, suggest that palbociclib inhibits nonhomologous end-joining repair of double-strand breaks. Inhibition of double-strand break repair by palbociclib is most evident in tumor cells treated with palbociclib during and after irradiation.…”

“…Potential benefit from the use of palbociclib with RT has been shown in preclinical studies of noncentral nervous system cancer 28,29 as well as in preclinical studies of 2 other types of brain tumors that occur predominantly in the pediatric population (ie, medulloblastoma 30 and brainstem glioma 31 ). Our results build upon the observations of these studies-as well as our previous study of GBM 5 -by showing that the timing of palbociclib treatment relative to the administration of radiotherapy could prove important for maximizing the benefit from inhibiting CDK4/6 in association with RT.…”

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

“…[5][6][7][8][9][10][11] We analyzed the combinatorial effects of palbociclib with the commonly used chemotherapy agents against CRC, as a prelude to possible translation. Chou-Talalay analysis revealed that palbociclib can synergize with a variety of chemotherapies under hypoxia (Fig.…”

“…6,7 A combined pharmacological inhibition of MEK and CDK4/6 led to substantial synergy in KRAS-mutated NSCLC in vivo. 8 Synergy of palbociclib with a MEK inhibitor has also been demonstrated in KRAS mutant colon cancer in vivo. 9,10 Vemurafenib-resistant tumors remain sensitive to palbociclib suggesting that initial treatment with vemurafenib followed by palbociclib with or without mTOR inhibitors might provide an approach to overcome recurrence of vemurafenibresistant, metastatic tumors.…”

The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies

“…However, there are instances where it appears that the combinations result in a synthetic cytotoxic response. For example, the combination of MEK and CDK4/6 inhibitors in non-small cell lung cancer induces cell death in concert with cell cycle inhibition [112]. The exact mechanisms underlying each combinatorial sensitivity is likely conditioned by the underlying genetic features of the tumor, as the same drug combination can have differing effects based on the tumor model studied.…”