Lung cancer is a cause of cancer-related death that continues to be one of the leading causes of cancer death throughout the world each year, with approximately 1.8 million deaths [1], [2]. This has a high fatality rate due to its aggressive nature and often late stage of diagnosis [3], [4]. Lung cancer is broadly categorized into NSCLC, which accounts for approximately 85 % of cases, and SCLC [5]. Among these, adenocarcinoma is the most common histological subtype of NSCLC and is the most commonly associated with smoking [6], [7]. Despite early screening and targeted therapies, the prognosis for advanced lung cancer remains poor, and few patients survive beyond 5 years [8], [9]. A wide range of mutations driving lung cancer pathogenesis has been uncovered by genomic studies, with KRAS mutations noticeably common [10]. RAS family member KRAS is a small GTPase transducing cell surface receptor signals to downstream pathways, including MAPK, PI3K, and RALGDS [11]. These signaling cascades are necessary for cellular function differentiation, survival, and proliferation [12]. KRAS activations where codon 12, 13, or 61 mutations occur constitutively activate KRAS and promote uncontrolled cell growth and cell survival [13], [14]. Lung adenocarcinomas are especially prone to KRAS mutations, occurring in about 25–30 percent of African Americans, for example, and in about 25–30 percent of Caucasians and Asians [15]. KRAS mutations are seen in the vast majority of patients with lung cancer and have high prevalence and oncogenic potential, thus underscoring the critical need for effective therapies to target this key regulator in lung cancer [16], [17].

An aggressive phenotype to KRAS mutations in lung cancer is associated with poor prognosis and resistance to therapeutic intervention [18]. Resistance to standard therapy (e.g., chemotherapy and radiotherapy) stems from constitutive activation of KRAS-driven signaling pathways, promoting a TME resistant to apoptosis and fostering cell survival [19]. Additionally, KRAS mutations are associated with poor outcomes and are frequently seen concurrently with other oncogenic mutations or tumor suppressor gene alterations, such as TP53 and STK11, complicating treatment strategies [20], [21]. Despite the partial efficacy of conventional small molecule inhibitors targeting KRAS mutations in clinical settings, monovalent inhibitors targeting the G12C mutation have failed [22]. However, their therapeutic value is often short-lived because cancer cells adapt quickly and activate compensatory signaling pathways or have acquired secondary mutations [23], [24]. Early resistance to G12C inhibitors such as sotorasib and adagrasib, exemplified by refitting KRAS pathways or other bypassing the inhibition of KRAS, limits the initial success [25]. Resisting these resistance challenges is possible but requires the development of new therapeutic strategies because KRAS mutations have been shown to limit the long-term effectiveness of current treatments and result in high recurrence in lung cancer patients who are KRAS mutants [26].

PROTACs currently represent a promising approach to developing cancer therapeutics for typically ‘undruggable’ proteins, including KRAS [27]. This PROTAC technology exploits the cell's ubiquitin-proteasome system to selectively degrade specific proteins using a bifunctional molecule [28]. A PROTAC molecule consists of two ligands connected by a linker. The E3 ubiquitin ligase recruiter will bind one ligand to the protein of interest (e.g., mutated KRAS) and then bind the other ligand that binds to the E3 ubiquitin ligase [29]. The target protein is made complex with this, allowing it to ubiquitinate and mark it for degradation by proteasome, removing the protein from the cell rather than just withholding function [30], [31]. The combined mechanism of PROTACs, compared with traditional small molecule inhibitors, offers several advantages, particularly for such proteins as KRAS that have no accessible binding pockets [32]. Unlike inhibitors, which rely on high affinity to block a protein’s function globally, PROTACs operate through event-driven pharmacology and allow for multiple rounds of target degradation for sustained inhibition of oncogenic signaling [33]. This approach may potentially overcome resistance mechanisms that prevent conventional treatments from being used. PROTACs represent a targeted and more durable therapeutic strategy targeting cancer-promoting pathways by depleting KRAS [34], [35].

This review aims to explore the potential of PROTAC technology in overcoming treatment resistance in KRAS-mutant lung cancer. We provide a comprehensive overview of KRAS mutations in lung cancer, their clinical significance, and their challenges in treatment. Furthermore, we examine recent advancements in PROTAC development, focusing on its application in targeting KRAS mutations and enhancing treatment efficacy.