Resistance to immune checkpoint inhibitors in KRAS-mutant non-small cell lung cancer

Abstract

Non-small cell lung cancer (NSCLC) patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation are associated with significant clinical heterogeneity and a poor prognosis to standard NSCLC therapies such as surgical resection, radiotherapy, chemotherapies, and targeted medicines. However, the application of immune checkpoints inhibitors (ICIs) has dramatically altered the therapeutic pattern of NSCLC management. Clinical studies have indicated that some KRAS-mutant NSCLC patients could benefit from ICIs; however, the responses in some patients are still poor. This review intends to elucidate the mechanisms of resistance to immunotherapy in KRAS-driven NSCLC and highlight the TME functions altered by immunoinhibitors, immunostimulators, and cancer metabolism. These metabolic pathways could potentially be promising approaches to overcome immunotherapy resistance.

Keywords: KRAS mutation; Non-small cell lung cancer; cancer metabolism.; immune checkpoints inhibitors; tumor microenvironments.

Figure 1

A schematic figure of KRAS-driven signaling pathways in the regulation of immunomodulators. PI3K: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; AKT: serine/threonine kinase; MAPK: mitogen-activated protein kinase 1; ERK: extracellular signal-regulated kinase 2; PFK: phosphofructokinase; HIF1α: hypoxia inducible factor 1 subunit alpha; JNK: mitogen-activated protein kinase 8; mTOR: mechanistic target of rapamycin kinase; LDHA/B: lactate dehydrogenase A/B; YAP: yes1 associated transcriptional regulator; IRF2: interferon regulatory factor 2; STAT3: signal transducer and activator of transcription 3; NF-κB: transcription factor P65; MHCs: major histocompatibility complex.

Figure 2

A schematic figure of KRAS-driven signaling pathways in the regulation of metabolic signaling pathways. GLUT: Glucose transporters; HK: hexokinase; PFK: phosphofructokinase; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; AKT: serine/threonine kinase; MAPK: mitogen-activated protein kinase 1; ERK: extracellular signal-regulated kinase 2; PDH: pyruvate dehydrogenase; PGK: phosphoglycerate kinase 1; HIF1α: hypoxia inducible factor 1 subunit alpha; JNK: mitogen-activated protein kinase 8; mTOR: mechanistic target of rapamycin kinase; LDHA/B: lactate dehydrogenase A/B; YAP: yes1 associated transcriptional regulator; IRF2: interferon regulatory factor 2; STAT3: signal transducer and activator of transcription 3; NF-κB: transcription factor P65; HSL: hormone-sensitive lipase; COX: cyclooxygenase; SCD: stearoyl-CoA desaturase; FASN: FA synthetase; ACLY: ATP-citrate lyase; GLS: glutaminase.