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C.M. Lovly
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E10 - Targeting KRAS in Lung Cancer (ID 10)
- Event: WCLC 2013
- Type: Educational Session
- Track: Biology
- Presentations: 3
- Moderators:C.M. Lovly, E. Thunnissen
- Coordinates: 10/30/2013, 14:00 - 15:30, Parkside Auditorium, Level 1
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E10.1 - Biology (ID 418)
14:00 - 15:30 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Abstract
Biological function of RAS An activity that transforms mouse NH 3T3 cells in DNA from human cancers turned out to be present in human homologues of retroviral oncogenes found earlier. These genes were named as HRAS or KRAS according to the names of corresponding viruses; Harvey- or Kirsten- ratsarcoma viruses. The difference between RAS gene present in normal tissue and that in cancer tissue was a single missense point mutation either at codon 12 , and less frequently at codons 13 or 61. The third member of the RAS family gene, NRAS was identified one year later from a human neuroblastoma cell line, although its viral homologue was not identified. There is a tendency that a certain type of cancer uses a particular type of RAS gene; e.g. most RAS mutations in lung or pancreas cancer occur in KRAS gene, whereas most RAS mutations in bladder cancer occur in HRAS gene . RAS gene encodes for a 21kDa protein that toggles guanosine diphosphate (GDP)-bound inactive form to and from guanosine triphosphate (GTP)-bound active form because RAS has a GTPase activity. Guanine nucleotide-exchange factors (GNEFs) and RAS GTPase activating proteins (RAS-GAPs) positively and negatively regulate the amount of GTP bound RAS, respectively. Oncogenic point mutations either at codon 12,or less frequently at codons 13 or 61 make RAS impair its intrinsic GTPase activity and confer resistance to GAPs, thereby causing RAS to accumulate in its active GTP-bound state and sustained activation of RAS signaling. It is known that GTP-bound, active RAS interacts with more than 20 effector proteins and stimulates downstream signaling cascades. These effectors and corresponding functional outcomes include RAF (proliferation), RIN1 (endocytosis), PI3K (survival), PLCe (second messenger signaling), RalGEF (endocytosis). Rather paradoxically, oncogenic RAS has been shown to cause senescence in primary cell culture through the activation of the WAFp21-p53 or p16-Rb pathways. It is also known that, to acquire its biological and transforming activities, RAS proteins should be bound to inner surface of the plasma membranes by appropriate post-translational modification. This process includes farnesyltation, proteolytic cleavage of AAX motif, carboxymethylation of the terminal Cys and palmitoylation. This process was initially thought to be a target of therapeutic intervention. However, inhibition of farnesyl transferase results in alternative geranylgeranylation of RAS which supports membrane binding. RAS gene activation in lung cancer Frequent somatic mutation of the RAS gene in lung cancer was first identified in 1987. RAS mutation in lung cancer usually occurs in KRAS, although rare instances of HRAS or NRAS mutations are reported. Mutation of the KRAS gene usually occurs in adenocarcinoma, rarely in squamous cell carcinoma and almost never occurs in small cell lung cancer. KRAS mutations predominantly occur in Caucasian patients (~30%) rather than East Asians (~10%). Association between KRAS mutation and smoking exposure has been reported back in 1991. KRAS mutation at codon 12 in lung cancer is characterized by the frequent a G to a T transversion in contrast to the frequent a G to a A transitions found in colorectal cancer. Even within lung cancer, more than half of KRAS mutations in smokers are either G12C (GGT-TGT) or G12V (GGT-GTT), while those in never smokers are G12D (GGT-GAT). It is thought that not all the KRAS mutations are created equal. There is a report that G12V has a weaker GTPase activity than G12D, suggesting stronger oncogenic activity of G12D. It is also generally believed that KRAS codon 13 mutation is weaker oncogene than codon 12 mutation. In terms of effect of cetuximab in colon cancer, tumors with G13D behaves like those with WT KRAS. Prognostic impact of KRAS mutations in lung cancer are variably reported, but in general it is thought to be a weak negative prognostic factor. Whether there is a difference in prognostic impact among different KRAS mutations remains to be elucidated. In terms of histologic types, KRAS mutations are associated with lung adenocarcinoma with mucus production / goblet cell morphology. Lung cancer with KRAS mutations often accompanies with CK20 and CDX2. These phenotypes are commonly observed in colorectal, pancreato-biliary, and ovarian mucinous carcinomas. How to cope with KRAS mutated lung cancer Although KRAS mutations occur in mutually exclusionary fashion with activation of other driver oncogenes such as EGFR, ALK, ROS1, RET, etc, it appears that not all cancers with KRAS mutations are dependent on mutant KRAS. Upon treatment of shRNAs to deplete KRAS in lung cancer cell lines harboring KRAS mutations, half of the cell lines maintained viability without expressing KRAS. This makes it difficult to develop treatment strategy against KRAS mutated tumors.. Although MEK-ERK signaling is an essential downstream of mutant KRAS, single treatment of MEK inhibitor exhibits variable responses and PI3K pathway activation strongly influences its sensitivity. Therefore, simultaneous downregulation of MEK-ERK and PI3K-AKT may have potential therapeutic value. Recent approach is to identify synthetic lethal interactions in cancer cells harboring KRAS mutation. In other words, it is to find which genes, when silenced, kill cells harboring mutant RAS gene but not cells without this mutation. However, the list of genes with synthetic lethal activity against RAS mutated tumors are expandingand includes THOC1, eNOS, Myc, Survivin, STK33, PLK1, SYK, RON, integrin b6, TBK1, NFkB, WT1, PKC delta, CDK4, JNK, ATR, GATA2. However, a subsequent and comprehensive study could not reproduce the synthetic lethal activity of STK33, throwing out the caveat that one should be cautious to interpret the RNAi data because individual shRNA can downregulate tens or hundreds of off-target genes . Above-mentioned experimental evidence suggests that RAS collaborate with many different molecules depending on cellular contexts to have oncogenic activity. This is why the development of RAS-targeted therapy is difficult and suggests that it would be necessary to develop combination therapy depending on different cellular context.Only Members that have purchased this event or have registered via an access code will be able to view this content. 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E10.2 - Predictive or Prognostic Role of KRAS (ID 419)
14:00 - 15:30 | Author(s): F. Shepherd
- Abstract
- Presentation
Abstract
KRAS mutations are found in ~30% of adenocarcinomas and ~5% of squamous NSCLC. They are more common in current or former smokers. Most KRAS mutations in NSCLC occur on codon 12 and less frequently codons 13 and 61. Prognostic Value of KRAS The prognostic significance of KRAS has been investigated extensively. Results have been inconsistent with heterogeneity among studies including differing endpoints and patient populations studied. A large meta-analysis of 28 studies reported that KRAS mutation was a negative prognostic factor for OS (p=0.01) when all cancers were considered, in adenocarcinoma (HR 1.52, CI 1.30-1.78, p=0.02) but not squamous histology (HR 1.49, CI 95%: 0.88–2.52; p=0.48). The International Agency for Research on Cancer assessed KRAS in 762 patients with resected NSCLC. Mutations were detected in 18.5%; KRAS was not prognostic for PFS (p=0.26). The LACE-Bio group performed a pooled analysis of 1,543 patients from four randomized trials of adjuvant chemotherapy vs observation. KRAS mutations were present in tumors of 300 patients (codon 12 275, codon 13 24, and 1 codon-14). This was the first study to assess the prognostic effect of different KRAS mutations. In observation patients, there was no prognostic difference for OS for codon-12 (HR=1.04) or codon-13 (HR=1.01) mutations, nor for specific codon-12 amino acid substitutions. KRAS was not prognostic in the adenocarcinoma subgroup (HR=1.0, p=0.97). This group was the first to report that OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR=2.76, p=0.005). This observation requires validation. Predictive Value of KRAS Mutation for Chemotherapy Several studies have assessed the predictive value of KRAS in NSCLC patients treated with chemotherapy, but few have had untreated control arms to be able to isolate the predictive from the prognostic effects of mutation status. Rodenhuis et al. assessed KRAS in 83 patients with advanced adenocarcinoma treated with ifosfamide/carboplatin/etoposide; 26% had mutations.[10 ]The presence of KRAS mutation was not significantly associated with response rate, PFS or OS (p=0.486, p=0.22 and p=0.29, respectively). The TRIBUTE trial in advanced NSCLC compared first-line carboplatin/paclitaxel +/- erlotinib. KRAS mutations were present in 21% of samples tested. Response rates in the chemotherapy-alone arm were 26% and 23% for patients with wild-type and mutated KRAS, respectively, with no significant survival difference (median OS 13.5 and 11.3 months, respectively). In a neo-adjuvant chemotherapy study, Boermann et al[12] reported ORRs of 80% and 77% in patients with KRAS wild-type and mutated tumors, respectively. PFS was longer in patients with wild-type tumors compared to those with mutations (PFS 21 vs 9 mo, p=0.003) although there was no difference in OS (p=0.07). The LACE-BIO pooled analysis revealed no significant effect of KRAS mutation on benefit from adjuvant chemotherapy with respect to OS or DFS, even in adenocarcinoma (interaction p=0.99). Analysis by KRAS subtype revealed a non-significant benefit from ACT in patients with wild-type KRAS (HR=0.89, p=0.15) but not codon-12 mutations (HR=0.95, p=0.77); with codon-13 mutations, ACT was deleterious (HR=5.78, p=0.001, interaction p=0.002). There was a trend towards benefit from ACT for codon-12 G12A or G12R (HR=0.66 p=0.48) but not G12C or G12V (HR=0.94 p=0.77) or G12D or G12S (HR=1.39 p=0.48), (comparison of 4 HRs, including WT p=0.76). Predictive Value of KRAS Mutation for Epidermal Growth Factor Receptor Inhibitors In TRIBUTE, patients with KRAS mutant tumors who received chemotherapy+erlotinib had shorter median TTP than those treated with chemotherapy+placebo (3.4 vs 6 months, p=0.03). OS also was significantly shorter in the KRAS mutant subgroup treated with chemotherapy+erlotinib than those treated with chemotherapy+placebo (4.4 vs 13.5 months, p=0.019). In the NCIC CTG BR.21 trial of erlotinib vs placebo in advanced NSCLC, KRAS mutations were found in 15% of response-evaluable patients in the erlotinib arm. Response rates were 10% and 5% for patients with wild-type and mutated KRAS, respectively (p=0.69). There was no significant difference in survival benefit from erlotinib based on KRAS status (interaction p=0.09) on multivariable analysis (p=0.13), despite a trend in univariate analyses (KRAS mutant HR 1.67, p=0.31; KRAS wild-type HR 0.69, p=0.03). In the ATLAS trial that compared maintenance bevacizumab+placebo to bevacizumab+erlotinib, 93 patients had tumors with KRAS mutations. There was no significant PFS benefit for bevacizumab+erlotinib (HR 0.93, p=0.7697), while in wild-type KRAS, there appeared to be some benefit for the combination (HR 0.67, p=0.01).[14] In the SATURN trial, stable and responding patients were randomized to receive maintenance erlotinib or placebo. KRAS mutation was detected in 18%. Modest PFS benefit from erlotinib was seen both in patients with mutant KRAS and wild-type tumors (interaction p=0.95). Data are limited regarding KRAS mutation subtype and response to EGFR-TKIs in NSCLC. One recent investigation of KRAS mutation status and response to EGFR-TKI in EGFR wild-type advanced NSCLC demonstrated that patients with codon 13 KRAS mutations had worse PFS (p=0.04) and OS (p=0.005) than patients with codon 12 mutations. However, there were only 14 and four patients having mutations in codons 12 and 13, respectively. Two meta-analyses have evaluated the association between KRAS and EGFR TKIs in NSCLC. Linardou et al. assessed 17 trials (1008 patients, 165 with KRAS mutation). Mutation was significantly associated with lack of response to TKIs. Mao et al. included 22 studies; 16% (231/1470) had KRAS mutations. ORRs were higher for KRAS wild-type compared to mutation (26% and 3%, respectively). The pooled relative risk for response was 0.29 (p<0.01). In Asians, relative risk was 0.22 (p=0.01), and 0.31 (p<0.01) in Caucasians. In BMS-099, advanced NSCLC patients were randomized to receive taxane/carboplatin +/- cetuximab. KRAS mutations were found in 17% of assessable samples. There was no significant association between KRAS status and response, PFS or OS. The FLEX study compared cisplatin/vinorelbine +/- cetuximab in EGFR-expressing NSCLC. KRAS mutations were detected in 19% of assessable samples. The addition of cetuximab to chemotherapy did not significantly affect survival, PFS or response in patients with KRAS wild-type or mutated tumors. Summary KRAS is at most, a weak prognostic marker in NSCLC. It should not be considered a tool to select patients for treatment at this time.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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E10.3 - Targeting KRAS and KRAS Signaling in the Clinic (ID 420)
14:00 - 15:30 | Author(s): G. Riely
- Abstract
- Presentation
Abstract not provided
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Author of
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MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:S. Lu, P. Waring
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside 204 A+B, Level 2
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MO01.07 - Inhibition of the IGF-1R signaling pathway potentiates responses to ALK inhibitors in both ALK TKI naive and ALK TKI resistant lung cancer (ID 1660)
10:30 - 12:00 | Author(s): C.M. Lovly
- Abstract
- Presentation
Background
Oncogenic fusions involving the gene encoding the anaplastic lymphoma kinase (ALK) define a new clinically relevant molecular subset of lung cancer. The majority of patients with ALK+ lung cancer are highly responsive to ALK tyrosine kinase inhibitor (TKI) therapy, however, the efficacy of these ALK inhibitors is limited by the development of acquired resistance. Additional strategies using rationally selected therapeutic agents/combinations of agents are needed to both delay and overcome acquired resistance to ALK inhibition. Based upon an intriguing clinical observation from a patient with ALK+ lung cancer who had an ‘exceptional response’ to an IGF-1R monoclonal antibody (MAb), we report a novel therapeutic synergism between ALK inhibitors and IGF-1R inhibitors.Methods
A series of experimental approaches including cell culture models, in vitro assays, and a study of patient tumor samples prior to and at the time of acquired resistance to ALK TKI therapy were employed to test the hypothesis that IGF-1R can be targeted therapeutically to enhance anti-tumor responses in ALK+ NSCLC.Results
Across multiple different ALK+ lung cancer cell lines, including a novel ALK+ cell line developed from a patient prior to ALK TKI therapy, IGF-1R inhibitors (TKIs and MAbs) sensitized ALK+ lung cancer cells to the effects of ALK blockade as assessed by standard cell viability assays. Similar to IGF-1R, ALK fusions co-immunoprecipitated with the adaptor protein, IRS-1, and treatment with ALK inhibitors decreased IRS-1 protein levels. Furthermore, siRNA mediated knock-down of IRS-1 impaired the proliferation of ALK+ lung cancer cells and enhanced the anti-tumor effects of ALK inhibitors. The IGF-1R pathway was activated in cell culture models of ALK TKI resistance, and combined ALK/IGF-1R inhibition in the resistant cells blocked reactivation of downstream signaling and markedly improved therapeutic efficacy in vitro. Finally, IGF-1R and IRS-1 levels were increased in biopsy samples from a patient with advanced ALK+ lung cancer post crizotinib therapy.Conclusion
Collectively, these data support a role for the IGF-1R/IRS-1 signaling pathway in both the ALK TKI sensitive and ALK TKI resistant states and suggest that this rationally selected combination of inhibitors may be an effective strategy to attempt to delay or overcome acquired resistance to therapeutic ALK inhibition. Intriguingly, the ‘second generation’ ALK TKI, LDK-378, which has demonstrated an overall response rate of 70% in patients with both crizotinib naïve and crizotinib resistant ALK+ lung cancer, can inhibit both ALK and IGF-1R in vitro. We speculate, based on these data, that this surprising response rate may be due to LDK-378’s ability to simultaneously inhibit both targets.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
