Prognostic implications of RAS alterations in diverse malignancies and impact of targeted therapies

Abstract

RAS alterations are often found in difficult-to-treat malignancies and are considered "undruggable." To better understand the clinical correlates and coaltered genes of RAS alterations, we used targeted next-generation sequencing (NGS) to analyze 1,937 patients with diverse cancers. Overall, 20.9% of cancers (405/1,937) harbored RAS alterations. Most RAS-altered cases had genomic coalterations (95.3%, median: 3, range: 0-51), often involving genes implicated in oncogenic signals: PI3K pathway (31.4% of 405 cases), cell cycle (31.1%), tyrosine kinase families (21.5%) and MAPK signaling (18.3%). Patients with RAS-altered versus wild-type RAS malignancies had significantly worse overall survival (OS; p = 0.02 [multivariate]), with KRAS alterations, in particular, showing shorter survival. Moreover, coalterations in both RAS and PI3K signaling or cell-cycle-associated genes correlated with worse OS (p = 0.004 and p < 0.0001, respectively [multivariate]). Among RASaltered patients, MEK inhibitors alone did not impact progression-free survival (PFS), while matched targeted therapy against non-MAPK pathway coalterations alone showed a trend toward longer PFS (vs. patients who received unmatched therapy) (HR: 0.79, 95% CI: 0.61-1.03, p = 0.07). Three of nine patients (33%) given tailored combination therapies targeting both MAPK and non-MAPK pathways achieved objective responses. In conclusion, RAS alterations correlated with poor survival across cancers. The majority of RAS alterations were accompanied by coalterations impacting other oncogenic pathways. MEK inhibitors alone were ineffective against RAS-altered cancers while matched targeted therapy against coalterations alone correlated with a trend toward improved PFS. A subset of the small number of patients given MEK inhibitors plus tailored non-MAPK-targeting agents showed responses, suggesting that customized combinations warrant further investigation. *S.M.L. and R.K. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

KRAS-Mutated, Estrogen Receptor-Positive Low-Grade Serous Ovarian Cancer: Unraveling an Exceptional Response Mystery

“…The molecular mechanisms underlying this exceptional response were elucidated by in vitro modeling that demonstrated that the known partial agonist/antagonist mechanism of tamoxifen compared with the estrogen depletion of letrozole was likely the critical feature that explained the different responses to the combination of each agent with an MEK inhibitor. It has previously been suggested that customized combination therapy may be a key to achieving tumor control when there are important genomic co‐alterations [9, 10], especially when certain gene product pathways, such as KRAS or PI3K, are activated [22]. Our current observations indicate that drugs with subtly different mechanisms of action targeting the same receptor may have markedly different anticancer activity when used in combinations.…”

Concomitant MEK and Cyclin Gene Alterations: Implications for Response to Targeted Therapeutics

“…Targeting one gene at a time for both cell cycle genes and RAS genes (other than KRAS G12C for which specific effective inhibitors are now in clinical trials (17,26,27,32)) has shown limited clinical efficacy. (13,33) Moreover, about 30% of tumors with RAS mutations are reported to have co-alterations in cell cycle genes, and about 5.5% of patients with diverse cancer harbor alterations in both BRAF/KRAS and cell cycle genes (136/2457) patients with Foundation Medicine tissue testing (Supplemental Figure 1) which may also explain why targeting only a single pathway can be challenging (14). As reported previously, targeting as many genomic alterations as possible can yield better clinical outcomes.…”

“…( 16) RAS and RAF alterations can potentially be targeted with drugs that inhibit one of the later steps, including MEK and ERK inhibitors, as well as specific inhibitors of KRAS G12C (for cancers that harbor a specific KRAS G12C mutation). (17,18) Importantly in this regard, we have recently demonstrated that survival was negatively impacted when patients had malignancies that demonstrated alterations in both RAS and cell cycle-associated genes as compared to patients with only one of these pathways altered, (14) and some authors hypothesize that co-targeting MEK and cyclin pathways might be important. (19,20) In an effort to evaluate the clinical impact of a genomic matching combination approach in patients whose advanced tumors harbor both MEK and cell cycle pathway abnormalities, we analyzed individuals who received concomitant MEK inhibitors and CDK inhibitors.…”

Neurotrophic tyrosine kinase inhibitors: A review of implications for patients, clinicians and healthcare services

“…Such therapies carry clear advantages as they generally lack the systemic side effects of traditional, nontargeted cytotoxic treatment options 4,5 and have revolutionised the outcomes of many malignant conditions. 6,7 NTRK genes code for three trans-membrane tropomyosin receptor kinases (TrkA, B and C) expressed primarily in neural tissue which all play significant roles in the development and function of the nervous system. 8 Activation of TRK by associated neurotrophins leads to phosphorylation of the receptor and activation of downstream cellular processes.…”

“…Such therapies carry clear advantages as they generally lack the systemic side effects of traditional, non-targeted cytotoxic treatment options 4,5 and have revolutionised the outcomes of many malignant conditions. 6,7…”