MINI REVIEW published: 13 January 2022 doi: 10.3389/fonc.2021.793121 Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies Marc Cucurull 1,2, Lucia Notario 1,2, Montse Sanchez-Cespedes 3, Cinta Hierro 1,2, Anna Estival 1,2, Enric Carcereny 1,2 and Maria Saigı́ 1,2* 1 Department of Medical Oncology, Catalan Institute of Oncology (ICO), Barcelona, Spain, 2 Badalona·Applied Research Group in Oncology (B·ARGO), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Barcelona, Spain, 3 Cancer Genetics Group, Josep Carreras Leukemia Research Institute (IJC), Barcelona, Spain Approximately 20% of lung adenocarcinomas harbor KRAS mutations, an oncogene that drives tumorigenesis and has the ability to alter the immune system and the tumor immune Edited by: microenvironment. While KRAS was considered “undruggable” for decades, specific Laura Mezquita, Hospital Clı´nic de Barcelona, Spain KRAS G12C covalent inhibitors have recently emerged, although their promising results Reviewed by: are limited to a subset of patients. Several other drugs targeting KRAS activation and Matthias Scheffler, downstream signaling pathways are currently under investigation in early-phase clinical University Hospital of Cologne, Germany trials. In addition, KRAS mutations can co-exist with other mutations in significant genes in Mohamed I. Saad, cancer (e.g., STK11 and KEAP1) which induces tumor heterogeneity and promotes Hudson Institute of Medical Research, different responses to therapies. This review describes the molecular characterization of Australia KRAS mutant lung cancers from a biologic perspective to its clinical implications. We aim *Correspondence: Maria Saigı´ to summarize the tumor heterogeneity of KRAS mutant lung cancers and its immune- msaigi@iconcologia.net regulatory role, to report the efficacy achieved with current immunotherapies, and to overview the therapeutic approaches targeting KRAS mutations besides KRAS Specialty section: This article was submitted to G12C inhibitors. Thoracic Oncology, Keywords: KRAS, NSCLC, ICI, PD-L1, STK11 a section of the journal Frontiers in Oncology Received: 11 October 2021 Accepted: 21 December 2021 INTRODUCTION Published: 13 January 2022 Citation: After decades of research, the treatment efficacy of advanced lung cancer has remarkably improved, Cucurull M, Notario L, by incorporating novel therapeutic strategies including targeted therapies inhibiting specific Sanchez-Cespedes M, Hierro C, genetically activated proteins, or immunotherapies such as immune-checkpoint inhibitors (ICI) Estival A, Carcereny E and Saigı´ M (1). Mutations affecting members of the RAS family genes (KRAS, HRAS, NRAS) are the most (2022) Targeting KRAS in Lung Cancer frequent genetic alterations in human cancer, affecting about 27% of all tumors, including lung, Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS colorectal and pancreatic ductal adenocarcinoma, among others (2, 3). and Novel Therapeutic Strategies. Lung adenocarcinoma (LuAD) is a type of cancer with the largest number of oncogenic Front. Oncol. 11:793121. alterations that are therapeutically approachable (4). Approximately 20-25% of the LuADs doi: 10.3389/fonc.2021.793121 harbor KRAS mutations, most of them affecting codons 12 (~85%), 13 (~10%) or 61 (~5%). In Frontiers in Oncology | www.frontiersin.org 1 January 2022 | Volume 11 | Article 793121 Cucurull et al. Targeting KRAS Beyond G12C Inhibitors LuADs from smokers, the vast majority of KRAS mutations of sotorasib, this was based on the efficacy results of the phase I/II consist on guanine to thymine transversions, an effect that is CodeBreak-100 trial (NCT03600883) that reported an objective associated with the tobacco carcinogens (5). At the aminoacid response rate (ORR) of 32% and disease control rate (DCR) of level, most of these mutations replace the glycine (G) in codon 12 88% among lung cancer patients. Thus, sotorasib has the FDA- by a cysteine (C) (G12C) and occurs in almost 50% of KRAS approval for this clinical indication (9). On the other hand, data mutant tumors. On the other hand, KRAS mutations in never- from the phase I/II KRYSTAL-1 trial (NCT03785249) for smokers are less frequent, and the most prevalent changes adagrasib showed significant benefit with an ORR of 45%, involve nucleotide transitions that replace the glycine in codon although the study is still ongoing and definitive conclusions 12 by an aspartic acid (G12D) or a valine (G12V) (6, cannot be inferred (10). Many other drugs targeting KRAS 7) (Figure 1). activation and other parallel and downstream pathways, as well In contrast to other oncogenic proteins activated in cancer as immunotherapeutic strategies, are currently under and despite multiple attempts to harness it, KRAS was investigation in early-phase clinical trials (11). considered undruggable for a long time. The KRAS mutated Here, we aim to describe the tumor heterogeneity of KRAS proteins has a reduced capability to hydrolyze GTP or to interact mutant lung cancers and its immune-regulatory role, to report with the GTPase-activating proteins, maintaining the oncogene the efficacy with current immunotherapies, and to overview the and the downstream pathways constitutively activated. The lack therapeutic approaches targeting KRAS mutant tumors, other of specific inhibitors targeting the KRAS hydrophobic pocket than KRAS G12C inhibitors. and the complexity of downstream pathways have contributed to the challenge of developing effective therapeutic strategies (8). After years of study, novel KRAS selective inhibitors became available for the KRAS G12C mutant protein, enabling a covalent KRAS-MUTANT LUNG CANCER IS A binding that hinders downstream signaling, which led to HETEROGENEOUS DISEASE AND HAS A promising results in the clinical setting. Two specific KRAS CHARACTERISTIC IMMUNE- G12C inhibitors, first sotorasib (AMG510) and later adagrasib MICROENVIRONMENT (MRTX849), earned the breakthrough designation by the US Food and Drugs Administration (FDA), to treat metastatic lung Mutations on KRAS and on other actionable oncogenic drivers, cancer patients harboring that particular KRAS mutation who such as EGFR or ALK, are often mutually exclusive. However, have progressed to at least one prior systemic therapy. In the case they co-occur with mutations in important tumor suppressor FIGURE 1 | Simplified overview of KRAS mutant tumor, downstream/upstream KRAS pathways, its impact on the immune-microenvironment and family of drugs targeting KRAS mutant tumors. (*) In the inset box, the oncogenic mutations in codon 12 of KRAS and aminonacid changes. Figure has been created with BioRender.com. Frontiers in Oncology | www.frontiersin.org 2 January 2022 | Volume 11 | Article 793121 Cucurull et al. Targeting KRAS Beyond G12C Inhibitors genes, such as STK11 (also known as LKB1), KEAP1, TP53, or THE EFFICACY OF CURRENT CDKN2A, whose inactivation cooperates with KRAS in the IMMUNOTHERAPIES IN LUNG CANCERS oncogenic process and, thus, characterize the heterogeneous nature of KRAS mutant tumors (12, 13). In addition, the WITH KRAS MUTATIONS different KRAS mutated proteins differ on their biologic Besides the immune-related nature of KRAS driven tumors, the properties to hydrolyze GTP and to activate downstream smoking habit of patients with KRAS mutations has been signaling pathways, which determines the differences in their associated with higher tumor mutational burden (TMB), which therapeutic vulnerabilities (14, 15). might predict better responses to ICI (34, 35). Skoulidis et al. described a molecular classification of KRAS Mazieres et al. retrospectively evaluated a cohort of non-small mutant LuAD according to the presence of co-mutations in cell lung cancer (NSCLC) harboring different oncogenic driver tumor suppressor genes TP53 (~30%) and/or LKB1 (~30% each) mutations. Among them, the subset of KRAS mutant tumors (16). These co-mutation partners lead to variances in gene expressed higher rates of PD-L1 and responded better to ICI than expression and distinct patterns of inflammatory and immune- tumors with other oncogenic driver alterations (36). On the checkpoint molecules release, which models the tumor other hand, most phase 3 clinical trials evaluating all-comers microenvironment and promotes different responses to with NSCLC treated with ICI did not stratify by KRAS status, and therapies (12, 17). Because of this tumor heterogeneity, the only post-hoc analyses have been performed on that subset. The prognostic role of KRAS mutant cancers remains uncertain, following section compiles the evidence derived from although most studies report a major aggressive behavior of exploratory analyses of the most relevant phase 3 clinical trials this type of cancer (18–20). evaluating ICI and real-world data from retrospective cohorts of KRAS mutant tumors are characterized by enabling tumor NSCLC patients treated with ICI. cells to escape immunosurveillance as one of the hallmarks The efficacy of nivolumab has been reported in two of cancer (21). NF-kB, STAT3, and certain suppressive international studies. In the Italian Expanded Access Program inflammatory cytokines such as IL-6, IL-1b and GM-CSF, are out of the 530 patients who received 2nd or 3rd line nivolumab, key transducers of the immunosuppressive properties of KRAS 206 (39%) were positive for KRAS mutation. KRAS status did not driven tumors (22–24). Other mechanisms in this tumor type influence nivolumab efficacy in terms of ORR (20% vs 17%, p = consist in increasing the expression of immune-checkpoints (e.g., 0.39) nor DCR (47% vs 41%, p = 0.23) in patients with KRAS- PD-L1) to prevent T-cell effector functions, eliciting the release mutant tumors when compared to KRAS-wild type (wt). No of myeloid-derived suppressor cells, regulatory T cells, and M2- statistically significant differences were found in the median differentiated tumor-associated macrophages, all of which impair progression-free survival (mPFS) nor in the median overall antitumor immunity and facilitates tumor growth (25, survival (mOS) between both groups, although the 3-months 26) (Figure 1). PFS was significantly higher in KRAS-mutant patients (53% vs In preclinical mice models, Stk11/Kras mutant tumors produced 42%, p = 0.01) (37). On the other hand, in the phase 3 study abundant IL-6 and were associated with neutrophil accumulation CA209-057, patients who had progressed to previous platinum- and inflammatory cytokines with immunosuppressive properties in based chemotherapy (ChT), were randomized to receive either the tumor microenvironment, along with increased levels of T-cell nivolumab or docetaxel. Among the 582 patients studied, KRAS exhaustion markers, compared with normal lungs (27). was tested in 185 patients and 33% showed a KRAS mutation. Accordingly, KRAS/STK11-mutant tumors are associated to a When comparing the latter with KRAS-wt patients in the groups “cold immunophenotype” with lower T-cell infiltration and lower who received ICI, the hazard ratio (HR) for OS and PFS were rates of PD-L1 immunostaining, among other immunosuppressive 0.52 (95% confidence interval [CI]: 0.29-0.95) and 0.82 (95% CI: features. Lung cancer patients with this tumor genetic profile 0.47-1.43), respectively, in favor to KRAS mutant patients (38). showed a worse response to ICI than did patients with KRAS- Regarding pembrolizumab, the clinical outcomes of two mutant tumors without LKB1 co-mutations (27–30). phase 3 clinical trials including KRAS mutant population have More recently, STK11 inactivation in KRAS-mutant tumors, been reported. The KEYNOTE-042 trial (NCT0222089) has been shown to enhance the silencing of the STimulator of evaluated pembrolizumab compared to platinum-based ChT as INterferon Genes (STING) protein, in part through epigenetic first-line treatment for PD-L1 positive tumors. The exploratory mechanisms (31). STING is a key component of the innate analysis presented by Herbst et al. showed that, out of 301 immunity and acts as a sensor for double-strand DNA (dsDNA) patients, 22.9% harbored KRAS mutations (9.6% were KRAS in the cytosol from virus and pathogens, which mediates the type I G12C) and presented higher levels of PD-L1 and tissue TMB. interferon production (32). By silencing STING expression, KRAS/ Both mOS and mPFS favored KRAS mutant tumors when treated STK11-mutant tumors become insensitive to cytoplasmatic with pembrolizumab compared to KRAS-wt, with a HR of 0.42 dsDNA sensing, avoiding T-cell inflammation and promoting (95% CI: 0.22-0.81) and 0.51 (95% CI: 0.29-0.87), respectively the recruitment of exhausted T-cell lymphocytes. Thus, restoring (39). On the other hand, the KEYNOTE-189 trial evaluated STING expression or activation of the cyclic GMP–AMP synthase platinum-based ChT either alone or in combination with (cGAS)-STING pathway with STING agonists, could induce T cell pembrolizumab as first-line setting in advanced disease. infiltration and turn this subset of tumors into more Among 289 patients, 30.8% harbored a KRAS mutation and immunogenic, increasing the synergistic effects in combination 12.8% a KRAS G12C. These tumors also presented higher levels with ICI (33). of PD-L1 and higher tissue TMB. Pembrolizumab-based therapy Frontiers in Oncology | www.frontiersin.org 3 January 2022 | Volume 11 | Article 793121 Cucurull et al. Targeting KRAS Beyond G12C Inhibitors was associated with improved clinical outcomes in terms of OS, KRAS mutant tumors with no druggable genetic alteration (47). PFS, and ORR regardless of KRAS status (40). Finally, results Clinical trials addressed to KRAS mutant NSCLC non specific for from real-world data published by Frost et al. from a multicenter, KRAS G12C are listed in Table 1. retrospective study evaluated the efficacy of first-line Before the advent of KRAS G12C inhibitors, several strategies pembrolizumab in 119 patients with KRAS mutant LuAD with were tested to target the broad spectrum of KRAS mutant high PD-L1 expression (≥50%). Co-mutations in TP53 were also tumors, but most of them failed. Historically, the majority of evaluated, and patients with KRAS G12C/TP53 had significantly these strategies focused on downstream effectors. For instance, higher ORR (100% vs 27.3%; p = 0.003) and longer mPFS (33.3 the MEK inhibitor selumetinib combined with docetaxel showed vs 2.8 months; HR, 0.18; 95% CI: 0.06-0.53; p = 0.002) than good responses in early trials but failed to improve survival in a tumors with KRAS nonG12C/TP53 mutations (41), suggesting randomized phase 3 trial (48, 49). The cyclin-dependent kinase that KRAS G12C present better outcomes to immune-based (CDK4/6) inhibitor abemaciclib was also tested in a randomized therapies. Furthermore, Noordhof et al. reported another phase 3 trial against erlotinib but could not achieve its OS retrospective study that evaluated the outcomes of first-line primary endpoint (50). Combining downstream effector pembrolizumab in 595 patients with metastatic LuAD and inhibitors targeting MEK/PI3K demonstrated moderate high PD-L1 expression. KRAS mutations were found in 57% of responses but unacceptable toxicity profiles (51). Another the cases. Although not statistically significant, mOS with ICI therapeutic strategy focusing on the RAS family was the was higher in KRAS mutant patients than in those with KRAS-wt interruption of its anchoring to the cell membrane by (19.2 vs 16.8 months; p = 0.86) (42). inhibiting the post-translational farnesylation (e.g. tipifarnib). In relation to atezolizumab, efficacy results are derived from a Unfortunately, despite a seemingly effective strategy in early single trial, IMpower 150 (NCT02366143), a phase 3 study with phase trials, phase 2 and 3 trials assessing the effectivity in first-line ChT and bevacizumab in combination or not with KRAS mutant tumors could not meet the expected outcomes atezolizumab in patients with metastatic NSCLC. An exploratory (52). Hence, ChT remained the main treatment for these tumors analysis evaluated atezolizumab efficacy in KRAS mutant for a long time, albeit with limited success. population according to STK11/KEAP1 mutation status. Among Since KRAS mutant tumors form a heterogenous disease, 920 evaluable patients, 24.5% harbored a KRAS mutation, which nowadays, investigational efforts are focused on a subset of in 45% of the cases were co-mutated with STK11 and/or KEAP1. targeted therapies that can be further classified in different Greater benefits in terms of OS and PFS were observed in patients families according to their mechanism of action. Furthermore, harboring KRAS mutations in the immunotherapy-based arm, to achieve better outcomes, the different families can be regardless of STK11 and KEAP1 status (43). combined with themselves, with KRAS G12C inhibitors, or Finally, results on durvalumab in stage III NSCLC patients with immunotherapy. We will subsequently develop further after ChT-radiotherapy are available from a retrospective study each one of these potential options: that was carried out in 134 patients from MD Anderson Hospital. Patients with driver oncogenic mutations, including KRAS i) KRAS Mutation-Specific Inhibitors mutations (n=26) and targetable driver mutations (n=24) in Besides KRAS G12C inhibitors, no other point mutations of EGFR, ALK translocations, ROS1 fusions, MET exon 14 skipping, KRAS have been successfully targeted in human trials yet. RET fusion, and/or BRAF, had significantly worse mPFS However, the artificial cyclic peptide KS-58 enhanced anti- compared to those without driver mutations (n=84) (8.9 months cancer activity in vitro and in vivo in KRAS G12D mutant vs 26.6 months; HR 2.62 p < 0.001), particularly in cases with tumors by blocking intracellular Ras-effector protein KRAS mutant tumors (mPFS 7.9 months, HR 3.34, p < 0.001), interactions (53). Also, the new molecule MRTX1133 has with no impact on OS based on driver mutation status (44). shown promising results, binding to G12D in lung and pancreatic tumor models (54). ii) Pan-KRAS Inhibitors TARGETING KRAS BEYOND KRAS SOS1 is a guanine exchange factor for KRAS promoting the G12C MUTATIONS phosphorylation of GDP to GTP by binding to its catalytic site. Moreover, SOS1 can bind to the allosteric site of KRAS that KRAS is a GTPase that, when mutated, loses the ability to turn potentiates its GEF function, increasing its positive feedback back to the GDP-bound state and leads to a constitutively active regulation (54). SOS1 inhibition has demonstrated a depletion GTP-bound state. This, in turn, activates downstream signaling effect on tumors that depend on KRAS activation. Recently, a pathways, including MAPK, PI3K/AKT/mTOR, and Ras-like new potent and selective SOS1 inhibitor, BI-3406, has shown in GEF, among others, all of them responsible for cell vitro and in vivo antitumor activity (55). The drug decreased proliferation and survival (45, 46) (Figure 1). In addition, the GTP-loaded KRAS and attenuated feedback reactivation by heterogeneity of KRAS mutations results in a variety of different MEK inhibitors, suggesting that this combination may be a diseases, which hinders the finding of a unique common therapy promising treatment option. In fact, that specific combination to address all of them. Thus, while KRAS G12C specific was tested in vitro in cell lines resistant to KRAS G12C inhibitors inhibitors have proven efficacy against their target, many other with satisfactory results and is currently ongoing phase 1 trials therapeutic strategies are currently under development for those (56). SHP2 is a protein tyrosine phosphatase existing either Frontiers in Oncology | www.frontiersin.org 4 January 2022 | Volume 11 | Article 793121 Cucurull et al. Targeting KRAS Beyond G12C Inhibitors TABLE 1 | Clinical trials of drugs targeting KRAS. Therapeutic Family Clinical Trial Phase Drug Indication Results Pan-RASinh NCT03114319 1 TNO155 (SHP2i) alone or with nazartinib (EGFRi) EGFR/KRAS NSCLC, esophageal SCC, H/N N/A SCC, Melanoma NCT03634982 1 RMC-4630 (SHP2i) All solid tumors N/A NCT04045496 1 JAB-3312 (SHP2i) All solid tumors N/A Pan-RASinh NCT04111458 1 BI 1701963 (SOS1i) + trametinib (MEKi) KRAS NSCLC N/A +downstream inh NCT04916236 1 RMC-4630 (SHP2i) + LY3214996 (ERK1/2i) KRAS tumors N/A Pan- RASinh + IT NCT04000529 1b TNO155 (SHP2i) + ribociclib (CDK4/6i) or KRAS NSCLC N/A spartalizumab (PD1i) Downstream inh NCT03681483 1 RO5126766 (RAF/MEKi) KRAS NSCLC N/A Downstream inh NCT02857270 1 LY3214996 (ERK1/2i) alone or + other drugs All solid tumors N/A combination NCT03284502 1b HM95573 (RAFi) + cobimetinib (MEKi)or cetuximab All solid tumors N/A (EGFRi) NCT03170206 1/2 palbociclib (CDK 4/6i) + binimetinib (MEKi) KRAS NSCLC N/A NCT04620330 2 VS-6766 (RAF/MEKi) + defactinib (FAKi) G12V or other KRAS NSCLC N/A NCT02974725 1 LXH254 (RAFi) + LTT462 (ERK1/2i) or trametinib KRAS and BRAF tumors N/A (MEKi) or ribociclib (CDK4/6i) Downstream inh + NCT01229150 2 selumetinib NSCLC ORR 10% vs Upstream inh (MEKi) + erlotinib 0% (EGFRi) OS 21.8 vs vs selumetinib 10.5 months NCT02230553 1/2 trametinitb (MEKi) + lapatinib (Erbb1-2i) KRAS NSCLC N/A NCT03704688 1/2 trametinib (MEKi) + poniotinib (VEGFi) KRAS NSCLC N/A NCT04967079 1 trametinib (MEKi) + anlotinib (panRTKi) KRAS NSCLC N/A NCT01859026 1/2. MEK162 (MEKi) + erlotinib KRAS or EGFR tumors N/A NCT04965818 1b/2 futibatinib (FGFRi) + binimetinib (MEKi) KRAS tumors N/A Downstream inh + NCT04735068 2 binimetinib (MEKi) + hydroxychloroquine KRAS NSCLC N/A autophagy inh NCT04892017 1 DCC-3116 (ULK 1/2i) + trametinib (MEKi) RAS-RAF mutant all solid tumors N/A Autophagy inh NCT03095612 1/2 selinezor (XPO1i) + docetaxel KRAS NSCLC N/A Downstream inh + IT NCT02779751 1b pembrolizumab (PD1i) + abemaciclib (CDKi) KRAS non squamous NSCLC, sq-NSCLC and N/A Luminal-like breast cancer NCT02779751 1b pembrolizumab (PDL1i) + abemaciclib (CDKi) KRAS non squamous NSCLC, sq-NSCLC and N/A Luminal-like breast cancer NCT03299088 1b pembrolizumab (PD1i) + trametinib (MEKi) KRAS NSCLC N/A Downstream inh + NCT03990077 1 HL-085 (MEKi) + docetaxel KRAS NSCLC N/A ChT mRNA vaccine NCT03948763 1 V941 (mRNA vaccine) All solid tumors N/A Metabolic modifier NCT03808558 2 TVB-2640 (FASNi) KRAS NSCLC N/A Inh/i, inhibitors; IT, immunotherapy; ChT, chemotherapy; NSCLC, non-small cell lung cancer; SCC, squamous cell carcinoma; ORR, overall response rate; N/A, non-assessed. bound to the cytoplasmatic portion of an activated RTK or as a approved but are expected to directly suppress the MAPK component of the RAS activating complex (57). SHP2 allosteric pathway’s effector node. When administered alone, only inhibitors, such as TNO155 and RMC-4630, have shown activity achieved disease stabilization and the phase I trial testing on ERK inhibition; ongoing trials combining both treatments are LT462 (NCT02711345) was terminated earlier. ERK inhibitors currently assessing their potential to overcome drug resistance to could further be combined with drugs targeting upstream RTK/RAS/MAPK inhibitors (58, 59). nodes in the MAPK pathway to reduce the incidence of iii) Downstream KRAS Inhibitors acquired resistance. Besides, the PI3K/mTOR/AKT pathway The immediate effect of activated RAS is the interaction between is a downstream pathway activated by the RAS family. In this the RAS switched region with the RAS binding domain (RBD) early phase clinical trial (NCT00933777), the combination of conserved in multiple proteins of multiple signaling pathways. sorafenib (a multi-TKI) with everolimus (mTOR inhibitor) A RAS mimetic small molecule, rigosertib, targets these RBD did not achieve any partial response in NSCLC patients by interrupting RAF, RALGDS, and PI3Ks signaling cascades harboring KRAS mutation, assessed by CT-scans (62). (60). So far, RAF and MEK inhibitors alone or in combination However, combinations of MEK and PI3K/mTOR/AKT with RTK inhibitors have failed to prove effective in KRAS inhibitors have demonstrated better efficacy in KRAS mutant tumors. However, a novel RAF/MEK potent inhibitor mutant LuADthan either one alone, but their potential showed a 60% tumor reduction in RAS-RAF mutated tumors toxicity has to be addressed by different treatment schemes and is being tested in combination with a FAK inhibitor in (e.g. intermittent dosage) (63, 64). KRAS mutant LuAD (61). ERK 1/2 inhibitors are yet to be iv) Upstream KRAS Inhibitors Frontiers in Oncology | www.frontiersin.org 5 January 2022 | Volume 11 | Article 793121 Cucurull et al. Targeting KRAS Beyond G12C Inhibitors KRAS-mutant tumors are still sensitive to extracellular growth strategies targeting KRAS. A deeper understanding of the factors and not completely independent of growth factor cancer biology and immune system interactions that fuel receptors (ERBB proteins), since both have a role in carcinogenesis in KRAS mutant tumors is essential for tumorigenesis (65). Their activity could be tackled by blocking developing new drugs and improving disease prognosis. upstream effectors and the combination of pan-Erbb family Besides KRAS G12C specific inhibitors, several other drugs inhibitors with KRAS pathway inhibitors could increase the targeting KRAS directly or indirectly are being investigated. In efficacy as well as contribute to overcome the drug resistance addition, the list of actionable KRAS mutations in lung cancer enhancing the outcomes observed with inhibiting each target will likely increase in the upcoming years. alone, although at cost of increased toxicities. Two preclinical Current immunotherapies seem to be effective for subset of studies further support the idea that mutant KRAS demands KRAS mutant tumors, due in part, by the influence of smoking activation of ERBB receptors to facilitate lung tumorigenesis (65, related nature of KRAS G12C mutations. The presence of co- 66). One approach was focused on combining KRAS inhibition mutations such as STK11 or KEAP1 shape the tumor immune with epidermal growth factor receptor (EGFR) TKIs, as the microenvironment and might has an impact on treatment efficacy. EGFR signaling pathway is often activated in tumor cells to Incorporating these genetic alterations in diagnostic panels as bypass KRAS inhibition. However, past clinical trials combining predictive markers represent a useful strategy for therapeutic MEK inhibitor, selumetinib with EGFR inhibitor, Erlotinib were decisions, including immunotherapy-based regimens. largely unsuccessful with an ORR of 10% (95% CI 2.1 to 26.3%) Finally, the genomic complexity of KRAS mutant tumors will in KRAS mutant patients (67). ultimately require tailored application of therapeutic approaches v) Cellular Metabolism and Autophagy and upcoming data from clinical trials will contribute to provide KRAS mutant tumors present a high glucose metabolism, so that, the most promising strategies. multiple glycolytic genes are upregulated and its suppression could prevent tumor growth (68). Autophagy is a strategy to overcome starvation in healthy cells and it has been observed to be increased in many cancer types. Autophagy prevents cells AUTHOR CONTRIBUTIONS from undergoing programmed cell death. Moreover, it has been Conceptualization, EC, MC, and MS. Writing—original draft shown that the RAF/MEK/ERK cascade leads to autophagy via preparation, MC, EC, and MS. Writing—review and editing, STK11/AMPkinase-activated (AMPK) protein that activates the MS-C, CH, LN, and AE. Supervision, MS, MC, EC, and MS-C. autophagy kinase 1 signaling axis (69). Combined inhibition of All authors have read and agreed to the published version of autophagy and MAPK signaling is nowadays being studied in the manuscript. phase 1 and 2 trials (NCT04892017) (70). FUNDING CONCLUSIONS This research received no external funding. MS is supported by a The high frequency of KRAS mutations in cancer justifies the Juan-Rodé s contract from the Instituto de Salud Carlos III multiple efforts invested in developing novel therapeutic (JR20/00015). Adenocarcinoma. Clin Cancer Res (2008) 14(18):5731–4. doi: 10.1158/1078- REFERENCES 0432.ccr-08-0646 1. Herbst RS, Morgensztern D, Boshoff C. The Biology and Management of Non-Small 8. 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Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek Squibb, AstraZeneca; Travel/expenses: Pfizer, Roche. MSC reports a sponsored JR, et al. BI-3406, a Potent and Selective SOS1-KRAS Interaction research agreement with Merck Serono Pharmaceuticals. CH reports research Inhibitor, Is Effective in KRAS-Driven Cancers Through Combined grants from Merck, and speaker’s bureau from MSD, Lilly and Ipsen. AE reports MEK Inhibition. Cancer Discov (2021) 11(1):142–57. doi: 10.1158/2159- honoraris from Roche, MSD, AstraZeneca and Pharmamar. Travel/expenses: 8290.CD-20-0142 Roche, MSD, AstraZeneca, Lilly, Pfizer, Pharmamar. EC reports advisory/ 57. Koga T, Suda K, Fujino T, Ohara S, Hamada A, Nishino M, et al. KRAS consultancy: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Secondary Mutations That Confer Acquired Resistance to KRAS G12C Novartis, Roche, Takeda. Speaker bureau: AstraZeneca, Boehringer Ingelheim, Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights Bristol-Myers Squibb. MSD, Novartis, Pfizer, Roche, Takeda, Amgen. Travel/ From in Vitro Experiments. J Thorac Oncol (2021) 16(8):1321–32. accommodation/expenses: Bristol Myers Squibb, Pfizer, Roche, Takeda. MS doi: 10.1016/j.jtho.2021.04.015 reports a sponsored research agreement with Merck Serono Pharmaceuticals. 58. Kerr DL, Haderk F, Bivona TG. Allosteric SHP2 Inhibitors in Cancer: Advisory/consultancy: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda; Travel/ Targeting the Intersection of RAS, Resistance, and the Immune expenses: Pfizer, Roche. Microenvironment. Curr Opin Chem Biol (2021) 62(1):1–12. doi: 10.1016/ j.cbpa.2020.11.007 The remaining author declares that the research was conducted in the absence of 59. LaMarche MJ, Acker M, Argintaru A, Bauer D, Boisclair J, Chan H, et al. any commercial or financial relationships that could be construed as a potential Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of conflict of interest. Cancer. J Med Chem (2020) 63(22):13578–94. doi: 10.1021/acs. jmedchem.0c01170 Publisher’s Note: All claims expressed in this article are solely those of the authors 60. Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, Baker SJ, Cosenza SC, and do not necessarily represent those of their affiliated organizations, or those of Basu I, et al. A Small Molecule RAS-Mimetic Disrupts RAS Association With the publisher, the editors and the reviewers. Any product that may be evaluated in Effector Proteins to Block Signaling. Cell (2016) 165(3):643–55. doi: 10.1016/ this article, or claim that may be made by its manufacturer, is not guaranteed or j.cell.2016.03.045 endorsed by the publisher. 61. Chenard-Poirier M, Kaiser M, Boyd K, Sriskandarajah P, Constantinidou A, Harris SJ, et al. Results From the Biomarker-Driven Basket Trial of Copyright © 2022 Cucurull, Notario, Sanchez-Cespedes, Hierro, Estival, Carcereny RO5126766 (CH5127566), a Potent RAF/MEK Inhibitor, in RAS- or RAF- and Saigı.́ This is an open-access article distributed under the terms of the Creative Mutated Malignancies Including Multiple Myeloma. J Clin Oncol (2017) 35 Commons Attribution License (CC BY). The use, distribution or reproduction in other (15_suppl):2506–6. doi: 10.1200/jco.2017.35.15_suppl.2506 forums is permitted, provided the original author(s) and the copyright owner(s) are 62. Nogova L, Mattonet C, Scheffler M, Taubert M, Gardizi M, Sos ML, et al. credited and that the original publication in this journal is cited, in accordance with Sorafenib and Everolimus in Patients With Advanced Solid Tumors and accepted academic practice. No use, distribution or reproduction is permitted which KRAS-Mutated NSCLC: A Phase I Trial With Early Pharmacodynamic FDG- does not comply with these terms. Frontiers in Oncology | www.frontiersin.org 8 January 2022 | Volume 11 | Article 793121