KRAS mutations are among the most common genetic alterations in lung, colorectal, and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a long-standing pursuit in precision ...oncology, one established shortly after the discovery of RAS mutations in human cancer cells nearly 40 years ago. Recent advances in medicinal chemistry have established inhibitors targeting KRAS(G12C), a mutation found in ∼13% of lung adenocarcinomas and, at a lower frequency, in other cancers. Preclinical studies describing their discovery and mechanism of action, coupled with emerging clinical data from patients treated with these drugs, have sparked a renewed enthusiasm in the study of KRAS and its therapeutic potential. Here, we discuss how these advances are reshaping the fundamental aspects of KRAS oncoprotein biology and the strides being made toward improving patient outcomes in the clinic.
Kim et al. review recent advances in the effort to therapeutically target KRAS(G12C), one of the most common oncoproteins in lung cancer and one previously thought to be undruggable. Mechanistic insights with implications for the emergence of resistance and optimal combination therapy are discussed.
RAF kinase inhibitors have substantial therapeutic effects in patients with BRAF-mutant melanoma. However, only rarely do tumors regress completely, and the therapeutic effects are often temporary. ...Several mechanisms of resistance to RAF inhibitors have been proposed. The majority of these cause ERK signaling to become insensitive to treatment with RAF inhibitors by increasing the amount of RAF dimers in cells, whereas others bypass the dependence of the tumor on mutant RAF. One motivation for studying mechanisms of drug resistance is that such efforts may suggest new therapeutic targets or rational combination strategies that delay or prevent the emergence of drug-resistant clones. Here, we review the current model of RAF inhibitor resistance with a focus on the implications of this model on ongoing laboratory and clinical efforts to develop more effective therapeutic strategies for patients with BRAF-mutant tumors.
It is thought that KRAS oncoproteins are constitutively active because their guanosine triphosphatase (GTPase) activity is disabled. Consequently, drugs targeting the inactive or guanosine ...5′-diphosphate–bound conformation are not expected to be effective. We describe a mechanism that enables such drugs to inhibit KRASG12C signaling and cancer cell growth. Inhibition requires intact GTPase activity and occurs because drug-bound KRASG12C is insusceptible to nucleotide exchange factors and thus trapped in its inactive state. Indeed, mutants completely lacking GTPase activity and those promoting exchange reduced the potency of the drug. Suppressing nucleotide exchange activity downstream of various tyrosine kinases enhanced KRASG12C inhibition, whereas its potentiation had the opposite effect. These findings reveal that KRASG12C undergoes nucleotide cycling in cancer cells and provide a basis for developing effective therapies to treat KRASG12C-driven cancers.
Recently reported to be effective in patients with lung cancer, KRAS
inhibitors bind to the inactive, or guanosine diphosphate (GDP)–bound, state of the oncoprotein and require guanosine triphosphate ...(GTP) hydrolysis for inhibition. However, KRAS mutations prevent the catalytic arginine of GTPase-activating proteins (GAPs) from enhancing an otherwise slow hydrolysis rate. If KRAS mutants are indeed insensitive to GAPs, it is unclear how KRAS
hydrolyzes sufficient GTP to allow inactive state–selective inhibition. Here, we show that RGS3, a GAP previously known for regulating G protein–coupled receptors, can also enhance the GTPase activity of mutant and wild-type KRAS proteins. Our study reveals an unexpected mechanism that inactivates KRAS and explains the vulnerability to emerging clinically effective therapeutics.
KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma
. KRAS(G12C) inhibitors
are in phase-I clinical trials and ...early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation
, and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes-or cells in which these changes are pharmacologically inhibited-remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic.
MEK inhibitors are clinically active in BRAFV600E melanomas but only marginally so in KRAS mutant tumors. Here, we found that MEK inhibitors suppress ERK signaling more potently in BRAFV600E, than in ...KRAS mutant tumors. To understand this, we performed an RNAi screen in a KRAS mutant model and found that CRAF knockdown enhanced MEK inhibition. MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAFV600E. MEK inhibitors induced RAF-MEK complexes in KRAS mutant models, and disrupting such complexes enhanced inhibition of CRAF-dependent ERK signaling. Newer MEK inhibitors target MEK catalytic activity and also impair its reactivation by CRAF, either by disrupting RAF-MEK complexes or by interacting with Ser 222 to prevent MEK phosphorylation by RAF.
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•KRAS mutant tumors are less sensitive to MEK inhibitors than are BRAFV600E mutant tumors•CRAF knockdown enhances the effect of MEK inhibitors•MEK is less susceptible to MEK inhibitors when activated by CRAF than by BRAFV600E•MEK inhibitors have distinct biochemical properties that control their activity
Lito et al. explain the disparate responses of BRAFV600E and KRAS mutant tumors to MEK inhibitors; they induce MEK-RAF complexes, resulting in rapid MEK reactivation by CRAF in the latter. Lito et al. show that more effective, newer MEK inhibitors inhibit both MEK catalytic activity and its reactivation by CRAF.
The ERK signaling pathway is one of the most commonly deregulated pathways in cancer. Assays that accurately measure ERK signaling output in clinical specimens would be extremely helpful not only in ...determining the pharmacodynamic effects of drug treatment but also in selecting those patients most likely to respond to therapy.
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Abstract Background Large cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers. Pathologic classification and optimal therapies are debated. We report the ...clinicopathologic features, treatment and survival of a series of patients with stage IV LCNEC. Materials and Methods Cases of pathologically-confirmed stage IV LCNEC evaluated at Memorial Sloan Kettering Cancer Center from 2006 to 2013 were identified. We collected demographic, treatment, and survival data. Available radiology was evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Results Forty-nine patients with stage IV LCNEC were identified. The median age was 64 years, 63% of patients were male, and 88% were smokers. Twenty-three patients (n = 23/49; 47%) had brain metastases, 17 at diagnosis and 6 during the disease course. Seventeen LCNEC patients (35%) had molecular testing, of which 24% had KRAS mutations (n = 4/17). Treatment data for first-line metastatic disease was available on 37 patients: 70% (n = 26) received platinum/etoposide and 30% (n = 11) received other regimens. RECIST was completed on 23 patients with available imaging; objective response rate was 37% (95% confidence interval, 16%-62%) with platinum/etoposide, while those treated with other first-line regimens did not achieve a response. Median overall survival was 10.2 months (95% confidence interval, 8.6-16.4 months) for the entire cohort. Conclusion Patients with stage IV LCNEC have a high incidence of brain metastases. KRAS mutations are common. Patients with stage IV LCNEC do not respond as well to platinum/etoposide compared with historic data for extensive stage small-cell lung cancer; however, the prognosis is similar. Prospective studies are needed to define optimum therapy for stage IV LCNEC.
The histologic transformation of adenocarcinoma (ADC) to squamous cell carcinoma (SCC), known as adeno-squamous transition or AST, is frequently observed in patients with lung cancer undergoing ...cancer therapy. In this issue, Tong and colleagues investigate genetic and epigenetic mechanisms that drive AST to confer resistance to KRAS inhibitors in preclinical models and patients.
The histologic transformation of adenocarcinoma (ADC) to squamous cell carcinoma (SCC), known as adeno-squamous transition or AST, is frequently observed in patients with lung cancer undergoing cancer therapy. In this issue, Tong and colleagues investigate genetic and epigenetic mechanisms that drive AST to confer resistance to KRAS inhibitors in preclinical models and patients.
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