A novel pharmacologically targetable metabolic mechanism driving resistance to epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors (TKIs) has been identified in preclinical models of lung cancer in a Chinese study led by scientists at Shanghai Jiao Tong University School of Medicine (SJTU).

"Our study has pioneered the identification of a nongenetic, pharmacologically targetable metabolic mechanism that drives resistance to EGFR TKIs in preclinical models," said study leader Liang Zhu, a professor in the Department of Pharmacology and Chemical Biology at SJTU School of Medicine in Shanghai.

Notably, the study also demonstrated that targeting the aldo-keto reductase family 1 member B1 (AKR1B1) overcame resistance to EGFR-targeted TKIs in lung cancer cell lines and in patient-derived xenograft (PDX) mice, the authors reported in the October 6, 2021, edition of Science Translational Medicine.

Lung cancer is the leading cause of global cancer-related death, with the advent of EGFR-targeting TKIs that achieve marked responses in EGFR-mutant lung cancer representing a major advance in targeted precision medicine.

However, patients ultimately acquire drug resistance and their disease progresses. More than half of those resistant to first- or second-generation EGFR TKIs have acquired the T790M secondary EGFR mutation, which can be overcome by second-line treatment with the third-generation EGFR TKI osimertinib (Tagrisso; AstraZeneca).

Given its potency against tumors with primary EGFR mutations while sparing wild-type EGFR cells, osimertinib has recently been used as first-line therapy for advanced EGFR-mutant non-small cell lung cancer (NSCLC).

NSCLC

"Compared with small cell lung cancers, early-stage NSCLCs are less sensitive to chemotherapy or radiation, with surgery being the treatment of choice," Zhu told BioWorld Science.

"However, unresectable advanced NSCLCs harboring targetable driving mutations, including EGFR, initially respond well to targeted therapies, but almost inevitably develop progress due to acquired drug resistance, including to osimertinib as first- or second-line therapy."

This represents a considerable clinical challenge, due to the current lack of effective additional therapeutic strategies.

Mechanisms of acquired TKI resistance may include secondary EGFR mutations or phenotypic changes, but many others are unidentified or untargetable, especially those for osimertinib resistance.

An improved understanding of resistance mechanisms could provide insights and assist development of additional therapeutic strategies to overcome or delay acquired TKI resistance.

In their new study, Zhu collaborated with SJTU professor Yin Shen and Hong-Zhuan Chen, a professor in the Shanghai University of Traditional Chinese Medicine, to investigate whether metabolic reprogramming, which is a hallmark of malignancy, may lead to drug resistance.

The research team showed that AKR1B1, which normally catalyzes reduction of carbonyl-containing compounds, interacted with and activated the signal transducer and activator of transcription 3 (STAT3) to upregulate the cystine transporter solute carrier family 7 member 11 (SLC7A11).

"This finding demonstrates that an AKR1B1-STAT3-SLC7A11 axis underlies resistance to TKIs and indicates the rationale for overcoming resistance by targeting this axis," Zhu said.

The interaction was shown to lead to enhance cystine uptake and flux to de novo glutathione synthesis, reactive oxygen species (ROS) scavenging, protection against cell death and EGFR TKI drug resistance in lung cancer cell lines and in PDX mouse models.

"Thus far, mechanisms of acquired EGFR TKI resistance have mainly been attributed to secondary mutations, activation of bypass track signaling pathways, or phenotypic changes," noted Zhu.

"The above metabolic changes in preclinical models indicate a possible new TKI resistance mechanism, namely metabolic reprogramming," he said.

Importantly, suppressing AKR1B1 with selective inhibitors was shown to restore the sensitivity of resistant cell lines to EGFR TKIs and delay resistance in lung cancer PDX mice.

These selective AKR1B1 inhibitors notably included the diabetes drug epalrestat, which has been clinically approved in several countries for treating diabetic neuropathy.

Epalrestat

"Previous research has shown that AKR1B1 can be targeted by repurposing epalrestat, on which we focused our investigation due to its repurposing value and translational potential," said Zhu.

"Epalrestat was shown to have marked synergism with sensitivity to EGFR TKIs gefitinib (Iressa; AstraZeneca), erlotinib (Tarceva) and osimertinib in resistant lung cancer cell line cultures," he told BioWorld Science.

"PDX tumors were initially shown to respond well to osimertinib treatment, but sensitivity was gradually lost after continuous administration and tumors had relapsed following 56 days of treatment."

However, "the addition of epalrestat to osimertinib therapy completely blocked tumor relapse until day 74 when the experiment ended," Zhu said.

"We have found a previously unrecognized, nongenetic, metabolic mechanism for acquired resistance to EGFR TKI treatment in lung cancers, indicating that metabolic rewiring may constitute a new avenue of mechanism for molecularly targeted drug resistance in solid tumors," concluded Zhu.

"The acquired vulnerability can also be exploited pharmacologically in a drug repurposing manner for resistance reversal, implying a translational potential," he added.

"This study also provides preclinical evidence that targeting this vulnerability is a promising strategy to overcome osimertinib resistance, which represents an urgently challenging unmet clinical need."

Looking forward, "we will explore whether this finding is a general mechanism for cancer drug resistance in extended targeted therapies and conventional chemotherapies, while a clinical trial of combining epalrestat with an EGFR TKI in NSCLC is also currently under consideration."