Implications of KRAS mutations in acquired resistance to treatment in NSCLC

Abstract

Rationale: KRAS is the most common and, simultaneously, the most ambiguous oncogene implicated in human cancer. Despite KRAS mutations were identified in Non Small Cell Lung Cancers (NSCLCs) more than 20 years ago, selective and specific inhibitors aimed at directly abrogating KRAS activity are not yet available. Nevertheless, many therapeutic approaches have been developed potentially useful to treat NSCLC patients mutated for KRAS and refractory to both standard chemotherapy and targeted therapies.The focus of this review will be to provide an overview of the network related to the intricate molecular KRAS pathways, stressing on preclinical and clinical studies that investigate the predictive value of KRAS mutations in NSCLC patients.

Materials and methods: A bibliographic search of the Medline database was conducted for articles published in English, with the keywords KRAS, KRAS mutations in non-small cell lung cancer, KRAS and tumorigenesis, KRAS and TKIs, KRAS and chemotherapy, KRAS and monoclonal antibody, KRAS and immunotherapy, KRAS and drugs, KRAS and drug resistance.

Keywords: KRAS; NSCLC; TKI; pharmacogenetics; treatment acquired resistance.

Figure 1. Complexity of KRAS signalling pathways

KRAS belongs to the Ras superfamily, a group of small GTP-binding proteins, and serves as a signal transducer from its tyrosine kinase receptors, that are engaged by autocrine and paracrine stimuli. In the active GTP-bound conformation, KRAS activates several effector molecules resulting in endocytosis, cell growth and proliferation, apoptosis, migration, and survival. Abbreviations: GF: growth factor; RTK: receptor tyrosine kinase; GRB: growth factor receptor-binding protein; GEF: guanine nucleotide exchange factor; GTP: guanosine triphosphate; GDP: guanosine diphosphate; KRAS: Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; GAP: GTPase activating protein; RalGEF: RAL-guanine nucleotide exchange factor; PLD: phospholipase D; BRAF: v-Raf murine sarcoma viral oncogene homolog B; Mek: Mitogen-activated protein kinase kinase; Erk: extracellular signal-related kinase; MSK1: mitogen- and stress-activated protein kinase; C-MYC: v-Myc avian myelocytomatosis viral oncogene homolog; CDK2/4: cyclin-dependent kinase 2/4; E2F: E2 transcription factor; Rb: retinoblastoma protein; TBK1: TANK Binding Kinase 1; NFKB: nuclear factor kappa-light-chain-enhancer of activated B cells; NFKBIA: NFKB inhibitor alpha; FAK: focal adhesion kinase; PI3K: phosphoinositide-3-kinase; AKT: v-Akt murine thymoma viral oncogene homolog 1; mTOR: mammalian target of rapamycin; LKB1: serine/threonine kinase 11; AMPK: AMP-activated protein kinase; HIF1: hypoxia-inducible factor 1; LOX: lysyl oxidase; FAK: focal adhesion kinase.

Figure 2. Steps towards KRAS membrane trafficking and localization

After KRAS synthesis in the cytoplasm, farnesyl transferases add a lipid tail at a CaaX tetrapeptide motif (C: amminoacid cysteine; aa: two aliphatic residues; X: a variable residue) on the C-terminus of inactive KRAS protein. Lonafarnib and tipifarnib may inhibit this step, interfering with KRAS membrane trafficking. On the other hand, KRAS signaling could be block by salirasib, that targets the localization of KRAS to the membrane. Abbreviations: KRAS: Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; CaaX: carboxyl-terminal.

Figure 3. Targeting downstream effectors of oncogenic KRAS

In NSCLC, the KRAS protein is often mutated (mutant KRAS) leading to the inactivation of its GTPase activity. The result is the constitutive activation of KRAS and, therefore, of the several effector pathways that are activated downstream of KRAS, with the RAF/MEK/ERK and PI3K/AKT/mTOR as the two pathways that have been studied most in detail. Sorafenib is a multitarget TKI which also inhibits BRAF protein, while trametinib and selumetinib acts against MEK protein. On the other hand, buparlisib and ridaforolimus have been used as PI3K and mTOR inhibitors, respectively. Independently, to these two best characterized pathways, the research focused on the inhibition of other targets. For example, ganetespib, defactinib and abemaciclib act against HSP90, FAK and CDK4, respectively. The goal of these drugs is to stop the tumorigenesis promoted by mutant KRAS. Abbreviations: RTK: receptor tyrosine kinase; Hsp90: heat shock protein 90; GTP: guanosine triphosphate; GDP: guanosine diphosphate; KRAS: Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; BRAF: v-Raf murine sarcoma viral oncogene homolog B; MEK: mitogen-activated protein kinase kinase; ERK: extracellular signal-related kinase; MSK1: mitogen- and stress-activated protein kinase; c-MYC: v-Myc avian myelocytomatosis Viral Oncogene Homolog; CDK2/4: cyclin-dependent kinase 2/4; E2F: E2 transcription factor; Rb: retinoblastoma protein; FAK: focal adhesion kinase; PI3K: phosphoinositide-3-kinase; AKT: v-Akt murine thymoma viral oncogene homolog 1; mTOR: mammalian target of rapamycin.