Oncotarget: Retaining nanomolar potency in lung cancer with therapy-refractory mutations


Oncotarget published "The acylfulvene alkylating agent, LP-184, retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy-refractory mutations" which reported that KEAP1 mutant NSCLCs further activate NRF2 and upregulate its client PTGR1. LP-184, a novel alkylating agent belonging to the acylfulvene class is a prodrug dependent upon PTGR1.

The authors hypothesized that NSCLC with KEAP1 mutations would continue to remain sensitive to LP-184. LP-184 demonstrated highly potent anticancer activity both in primary NSCLC cell lines and in those originating from brain metastases of primary lung cancers.

LP-184 activity correlated with PTGR1 transcript levels but was independent of mutations in key oncogenes and tumor suppressors.

Correlative analyses of sensitivity with cell line gene expression patterns indicated that alterations in NRF2, MET, EGFR and BRAF consistently modulated LP-184 sensitivity.

These correlations were then extended to TCGA analysis of 517 lung adenocarcinoma patients, out of which 35% showed elevated PTGR1, and 40% of those further displayed statistically significant co-occurrence of KEAP1 mutations.

The gene correlates of LP-184 sensitivity allow additional personalization of therapeutic options for future treatment of NSCLC.

The gene correlates of LP-184 sensitivity allow additional personalization of therapeutic options for future treatment of NSCLC.

Dr. Aditya Kulkarni from The Lantern Pharma, Inc. said, "KEAP1, KRAS, TP53 and STK11/LKB1 are among the commonly altered genes with considerable clinical prevalence in non-small cell lung cancers (NSCLC)."

The authors profiled primary and metastatic in vitro models of NSCLC for their sensitivity to LP-184 as well as standard of care agents, evaluated gene correlates of LP-184 response, and obtained evidence on in vivo anti-tumor effect of LP-184.

Mutated KEAP1 and concomitant decreased KEAP1 activity in cancer cells induces greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps, thereby rendering KEAP1 mutations predictive of chemotherapy resistance in NSCLC patients.

The identification of a trend toward detrimental overall survival among a subset of platinum-treated NSCLC patients harboring co-occurring KRAS and STK11 mutations could label a more aggressive molecular subtype of NSCLC.

Figure 6: Clinical data analyses from TCGA reveal distinct patient subgroups with elevated PTGR1 that are likely to be predicted responders to LP-184.

Figure 6: Clinical data analyses from TCGA reveal distinct patient subgroups with elevated PTGR1 that are likely to be predicted responders to LP-184. (A) Analysis of clinical data on 517 lung adenocarcinoma patients shows frequency of mutated genes across the observed PTGR1 relative gene expression range. The value adjacent to the highly mutated gene is a two-sided permutation test p-value of PTGR1 relative gene expression between driver mutated (red) and non-mutated (white) samples. (B) Analysis of clinical data on the same 517 lung adenocarcinoma patients as in (A) displays patient subsets by PTGR1 expression status, and mutational frequencies of selected driver genes within the PTGR1 elevated subset.

They therefore investigated LP-184 sensitivity in NSCLC cell lines harboring individual or concomitant mutations in KEAP1, KRAS, TP53 and STK11.

They sought to assess LP-184 activity in a panel of selected NSCLC adenocarcinoma cell lines, determine associations between genomic and transcriptomic profiles and responses of cell lines tested, and compare in vitro potency of LP-184 with that of approved chemotherapy agents.

The Kulkarni Research Team concluded in their Oncotarget Research Output, "Our key findings demonstrate that the alkylating agent LP-184 has nanomolar potency in several NSCLC cell lines and is more potent than selected approved alkylating chemotherapeutics. Additionally, LP-184 has the potential to target tumors with elevated PTGR1 regardless of presence of other co-occurring mutations but is especially found to be effective in the background of clinically significant KEAP1 mutations. We propose further evaluation of LP-184 in multiple PTGR1 high NSCLC settings that may not necessarily be mutually exclusive, including in highly prevalent KEAP1 and KRAS mutant tumors (Figure 6), and in patients with lack of actionable targets or resistance-related genes with no effective therapy options available."

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DOI - https://doi.org/10.18632/oncotarget.27943

Full text - https://www.oncotarget.com/article/27943/text/

Correspondence to - Aditya Kulkarni - [email protected]

Keywords - non-small cell lung cancer, acylfulvene, alkylating agent, PTGR1, LP-184

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