Selumetinib: A Promising Pharmacologic Approach for KRAS -Mutant Advanced Non-Small-Cell Lung Cancer

Abstract

Selumetinib is a potent and selective inhibitor of MEK1 and 2 that is currently being clinically developed for the treatment of several human malignancies. Initially administered as free-base suspension, a more convenient Hyd-sulfate capsule formulation has recently been developed. Phase I studies revealed that acneiform dermatitis was the dose-limiting toxicity of both the free-base and capsule formulation given two-times a day at the maximum tolerated doses of 100 and 75 mg, respectively, with the capsule formulation resulting into a significantly higher drug bioavailability. Importantly, as a MEK inhibitor, selumetinib could be particularly effective in tumors with a hyperactivated Ras/Raf/MEK/ERK pathway, which might be the case of KRAS-mutant non-small-cell lung cancers (NSCLCs). Accordingly, a recent randomized Phase II study evaluating docetaxel plus selumetinib or placebo in KRAS-mutant pretreated advanced NSCLC patients has demonstrated a significant improvement in terms of response rate, progression-free survival and patient-reported outcomes in favor of the combination arm. These positive results support further clinical evaluation of selumetinib in NSCLC, and confirmatory ongoing and future trials will assess its role according to KRAS-mutation status and in combination regimens with other targeted agents.

Synergistic interaction between MEK inhibitor and gefitinib in EGFR-TKI-resistant human lung cancer cells

“…When considering recent promising studies on highly selective small molecules, MEK1/2 inhibitors have been developed and have shown clinical activity in a number of malignancies, including NSCLC (12,13). In the present study, the MEK1/2 inhibitor, AZD6244, in combination with gefitinib was selected to investigate the efficacy of this treatment in NSCLC cell lines, particularly in gefitinib-resistant cells.…”

Overall Response to First-Line Tyrosine Kinase Inhibitor and Second-Line Chemotherapy Is Predictive of Survival Outcome in Epidermal Growth Factor Receptor-Mutated Adenocarcinoma

“…Half of this cohort would anticipate the upcoming second-line treatment at 9-10 months, whereas a minority (10∼20%) would achieve a PFS up to 20 months [1,2,3,5]. When dealing with TKI resistance, several options exist, including continuation of the same drug [6], local ablative therapy for oligoprogression followed by re-initiation of the same drug [7], combination of second-generation TKI and cetuximab [8], switching to third-generation TKI [9] or treatment with new molecular targeted agents based on the detection of ALK [10], ROS1 [11], KRAS [12,13] or BRAF [14,15], but conventional chemotherapy remains fundamental. However, the therapeutic efficacy of subsequent second-line chemotherapy still fluctuates widely [16,17,18,19,20].…”

Defining subpopulations of differential drug response to reveal novel target populations

“…Using a network-based segmentation algorithm coupled with biomarker detection (SEABED), we investigated well-established pharmacological targets and clinical biomarkers by comparing the response patterns for BRAF (SB590885) and MEK (CI-1040) inhibition, which expectedly reproduced subpopulations sensitive to both enriched for BRAF mutants [34][35][36] . In another example, SEABED compared EGFR/ERBB2 (afatinib) and MEK (selumetinib) inhibition to reveal expected biomarkers such as BRAF, KRAS and NRAS mutations for selumetinib [13][14][15][16] , and afatinib associated with EGFR and ERBB2 amplifications 37,38 . Interestingly, the more afatinib-resistant subpopulation was enriched for PI3KCA-activating mutation, which may cause acquired resistance 24 .…”

“…We present results from our platform, SEABED (SEgmentation And Biomarker Enrichment of Differential treatment response), to demonstrate how unsupervised machine learning can discover intrinsic partitions in the drug response measurements of two or more drugs that directly correspond to distinct pharmacological patterns of response with therapeutic biomarkers. Addressing the challenges in comparing the response of two drugs, SEABED initially assesses two gold standards with established clinical biomarkers, namely the differential response of a BRAF inhibitor and MEK inhibitor with anticipated BRAF and KRAS mutations [13][14][15][16] , and an EGFR inhibitor and MEK inhibitor with expected biomarkers of EGFR, ERBB2 and KRAS mutations [17][18][19][20] . Next, we systematically compare how different drugs targeting the MAPK and PI3K-AKT pathway yield different patterns of response within subpopulations.…”