Dataset Information

EGFR mutations and AKT phosphorylation are markers for sensitivity to combined MCL-1 and BCL-2/xL inhibition in non-small cell lung cancer.

ABSTRACT: Lung cancer is among the common and deadly cancers. Although the treatment options for late-stage cancer patients have continued to increase in numbers, the overall survival rates for these patients have not shown significant improvement. This highlights the need for new targets and drugs to more effectively treat lung cancer patients. In this study, we characterize the MCL-1 inhibitor maritoclax alone or in combination with a BCL-2/xL inhibitor in a panel of lung cancer cell lines. BCL-2 family proteins, phosphorylated proteins, and apoptosis were monitored following the treatments. We found that maritoclax was effective at inhibiting growth in these lung cancer cells. We also establish that cell lines with EGFR mutations were most sensitive to the combined inhibition of MCL-1 and BCL-2/xL. In addition, a high level of phosphorylated AKT (S473) was identified as a marker for sensitivity to the combination treatment. This work has defined EGFR mutations and AKT phosphorylation as markers for sensitivity to combined MCL-1 and BCL-2/xL targeted therapy and establishes a rationale to explore multiple BCL-2 family members in patients who are refractory to EGFR inhibitor treatment. Our data support the design of a clinical trial that aims to employ inhibitors of the BCL-2 family of proteins in lung cancer patients.

SUBMITTER: Rice SJ

PROVIDER: S-EPMC6544263 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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EGFR mutations and AKT phosphorylation are markers for sensitivity to combined MCL-1 and BCL-2/xL inhibition in non-small cell lung cancer.

Rice Shawn J SJ Liu Xin X Wang Hong-Gang HG Belani Chandra P CP

PloS one 20190531 5

Lung cancer is among the common and deadly cancers. Although the treatment options for late-stage cancer patients have continued to increase in numbers, the overall survival rates for these patients have not shown significant improvement. This highlights the need for new targets and drugs to more effectively treat lung cancer patients. In this study, we characterize the MCL-1 inhibitor maritoclax alone or in combination with a BCL-2/xL inhibitor in a panel of lung cancer cell lines. BCL-2 family ...[more]

PMID: 31150457

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Project description:An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of MCL1 as compared with BCL2 or BCL2L1 (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα+ tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα+ breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measured in situ using Mcl-1/Bim proximity ligation assays. Importantly, MCL1 gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression of BCL2 or BCL2L1 and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1-selective inhibitors for targeted tumor cell killing.Implications: Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class. Mol Cancer Res; 15(3); 259-68. ©2016 AACR.

Dataset Information

EGFR mutations and AKT phosphorylation are markers for sensitivity to combined MCL-1 and BCL-2/xL inhibition in non-small cell lung cancer.

Publications

EGFR mutations and AKT phosphorylation are markers for sensitivity to combined MCL-1 and BCL-2/xL inhibition in non-small cell lung cancer.

Similar Datasets

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