Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future

Abstract

Lung cancer is the most frequent cancer with an aggressive clinical course and high mortality rates. Most cases are diagnosed at advanced stages when treatment options are limited and the efficacy of chemotherapy is poor. The disease has a complex and heterogeneous background with non-small-cell lung cancer (NSCLC) accounting for 85% of patients and lung adenocarcinoma being the most common histological subtype. Almost 30% of adenocarcinomas of the lung are driven by an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. The ability to inhibit the oncogenic KRAS has been the holy grail of cancer research and the search for inhibitors is immensely ongoing as KRAS-mutated tumors are among the most aggressive and refractory to treatment. Therapeutic strategies tailored for KRAS⁺ NSCLC rely on the blockage of KRAS functional output, cellular dependencies, metabolic features, KRAS membrane associations, direct targeting of KRAS and immunotherapy. In this review, we provide an update on the most recent advances in anti-KRAS therapy for lung tumors with mechanistic insights into biological diversity and potential clinical implications.

Keywords: EGFR; KRAS; NSCLC; STK11; degraders; immunotherapy; lung adenocarcinoma; metabolic rewiring; p53; targeted therapy.

Figure 1

The two states of RAS family GTPases. GTP- and GDP-bound states are directed by GEFs and GAPs. GEFs stimulate the exchange of GDP to GTP, promoting activation of RAS (On). GAPs drive GTP hydrolysis and return to inactive GDP-bound status (Off). The thickness of the arrows indicates the strength of GTP binding as well as the (hyper)activation of downstream effectors. The red cross indicates the impairment of GTP hydrolysis. GEF: guanine nucleotide exchange factor; GAP: GTPase-activating protein; GTP: guanosine triphosphate; GDP: guanosine diphosphate; RAS: rat sarcoma proto-oncogene

Figure 2

KRAS signaling in non-small-cell lung cancer (NSCLC). Schematic presentation of signaling pathways initiated by oncogenic KRAS aberrations is illustrated in a simplified fashion. RAF: rat fibrosarcoma; MEK: mitogen-activated protein kinase kinase; ERK: extracellular regulated kinase; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; mTOR: mechanistic target of rapamycin kinase; RALGDS: Ral guanine nucleotide dissociation stimulator; KRAS: Kirsten rat sarcoma viral oncogene homolog; CDK4/6: cyclin-dependent kinase 4/6; RHOA: Ras homolog family member; FAK: focal adhesion kinase; IKK: IkappaB kinase; IκB: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor; NF-κB: nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells; Bad: BCL2-associated agonist of cell death; BCL-XL: B-cell lymphoma-extra large; RAL: Ras-like protein; PLD1: phospholipase D1; TBK1: TANK binding kinase 1; TIAM1: T lymphoma invasion and metastasis-inducing protein 1; RAC: Ras-related C3 botulinum toxin substrate 1; JNK: c-Jun N-terminal kinase.

Figure 3

Therapeutic approaches to tackle KRAS mutant NSCLC in patients. Selected compounds and their targets are listed. CDK4/6: cyclin-dependent kinase 4/6; Chk1: checkpoint kinase 1; CRBN: cereblon; PROTAC: proteolysis-targeting chimeras; VHL: von Hippel–Lindau disease tumor suppressor; HSP90: heat shock protein 90; RAF: rat fibrosarcoma; MEK: mitogen-activated protein kinase kinase; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; mTOR: mechanistic target of rapamycin kinase; KRAS: Kirsten rat sarcoma viral oncogene homolog; FAK: focal adhesion kinase; ERBB: human epidermal growth factor receptor; PD-1: programmed cell death protein 1; PD-L: programmed cell death 1 ligand; MAPK: mitogen-activated protein kinase.