KRAS Wild-Type Pancreatic Cancer: Decoding Genomics, Unlocking Therapeutic Potential

In this issue of Clinical Cancer Research, Singh and colleagues defined the genomic and clinical features of KRAS wild-type (WT) pancreatic cancers, a biologically distinct subtype of this malignancy (1). They demonstrated that KRAS WT cases frequently harbor alternative driver oncogenes, with enrichment for mitogen-activated kinase (MAPK) pathway alterations, which can be exploited with existing targeted therapies. Their findings support the routine genomic testing for all patients with pancreatic cancer and reveal opportunities for precision medicine for many patients with KRAS WT tumors.

Pancreatic cancer is projected to be the second leading cause of cancer-related mortality in the United States by 2040 (2). These tumors have a poor prognosis, and targeted therapy or immunotherapy has failed to demonstrate clinical benefit in biomarker-unselected trials. Genetic profiles of pancreatic cancer show a high prevalence of KRAS mutations (90% of cases) together with frequent inactivating alterations in the TP53, CDKN2A, and SMAD4 tumor suppressors (3). The emergence of selective KRAS^G12C and KRAS^G12D inhibitors represents a significant breakthrough, with these agents exhibiting impressive clinical efficacy (4–6). As these KRAS-targeting approaches advance in the clinic, it becomes increasingly important to recognize pancreatic cancer as a genetically heterogeneous disease. KRAS WT tumors are a relatively understudied subtype. A comprehensive understanding of their clinical and genomic underpinnings is needed. In this regard, the study by Singh and colleagues offers a practical roadmap, providing valuable insights that can be readily implemented in clinical settings (1).

Analysis of 795 exocrine pancreatic cancers from a single institution with a targeted multi-gene assay (7), identified 73 patients (9.2%) with KRAS WT tumors. They found 43.8% (32/73) of KRAS WT cases had MAPK pathway alterations. There were 18 BRAF alterations, most of which were known to be activating, including p.N486_P490del in-frame deletion (n = 9), BRAF^V600E mutation (n = 3), and BRAF fusion (n = 1). In addition, there were seven receptor tyrosine kinase (RTK) fusions, involving ROS1 (n = 2), NRG1 (n = 2), NTRK1 (n = 1), NTRK3 (n = 1), FGFR2 (n = 1), and seven other MAPK pathway alterations, including amplifications in EGFR (n = 1), ERBB2 (n = 1), and MET (n = 1). The authors also demonstrated proof-of-principle for sensitivity to MAPK pathway targeting in KRAS WT subsets. Organoid models derived from 2 patients with BRAF in-frame deletions responded to dual pan-RAF inhibitor (LY3009120) and MEK inhibitor (trametinib) treatment. A patient harboring a ROS1 fusion (SLC4A4::ROS1) demonstrated sustained clinical benefit with crizotinib and cabozantinib, targeted therapies with activity against ROS1, providing clinical evidence for the feasibility of this strategy. Although validation in a larger cohort is necessary, these findings highlight the utility of detecting driver alterations in the MAPK pathway in guiding patients with KRAS WT tumors to promising targeted therapies (Fig. 1).

Among the remaining 56.2% (41/73) KRAS WT tumors without a MAPK pathway alteration, 29.3% (12/41) harbored activating oncogenic alterations in other drivers including GNAS (n = 6), MYC (n = 2), PIK3CA, and CTNNB1. Preferential loss of the tumor suppressor PTEN was also observed in KRAS WT cases. While efforts have been made to target these oncogenic alterations (8, 9), most remain clinically undruggable to date or in the case of PI3K pathway inhibitors have had limited activity. Thus, further comprehensive preclinical studies are warranted to pave the way for therapeutic development for these cases. On the other hand, the researchers noted a higher occurrence of chromosomal deletions in DNA damage response (DDR) genes such as ATM, ATR, and CHEK1 in KRAS WT pancreatic cancers. These changes may serve as predictive markers for sensitivity to drugs affecting DNA repair, including PARP inhibitors (10). Interestingly, previous studies reported similar observations regarding DDR pathway, with KRAS WT cases demonstrating a slightly prolonged overall survival with platinum-based therapies, which was attributed to a higher frequency of mutations in DDR genes (11). Therefore, it may be interesting to explore the utility of targeting the DDR pathway in KRAS WT cases.

It is also noteworthy that drivers seen in KRAS WT cases aligned with some of the acquired resistance mechanisms to KRAS^G12C inhibitors, including BRAF-activating mutations and RTK fusions (12, 13). This suggests that there might be a convergence in the biology of these resistant tumors with KRAS WT disease. As the use of KRAS inhibitors increases, understanding the biology of tumors driven by KRAS-independent pathways becomes increasingly significant.

The researchers observed a number of distinct features of KRAS WT tumors. Compared with the KRAS mutant group, these cases showed better overall survival, earlier onset, improved overall survival with CDKN2A loss, and markedly worsened prognosis with SMAD4 loss. Because KRAS WT cases are heterogeneous subsets with various mutations, future studies are required to fully interpret these findings. Considering the substantial increase in early-onset pancreatic cancer (14, 15), it will be important to understand the functional relationship between KRAS WT status and early-onset. Moreover, while the progression of precursor lesions (pancreatic intraepithelial neoplasia) triggered by KRAS mutations has been thoroughly investigated, the precursors of KRAS WT pancreatic cancers remain less profiled. As Singh and colleagues pointed out, these tumors may more frequently emerge from the cystic pancreatic cancer progenitor, intraductal papillary mucinous neoplasm, as suggested by the enrichment of GNAS mutations (16). In this regard, our current preclinical research on pancreatic cancers heavily relies on mouse models or cell lines with KRAS mutations. Knowledge gained from alternative oncogene-driven models may hold even greater importance in the coming years.

Another valuable area of investigation includes insights into the effectiveness of immunotherapy in KRAS WT cancers. Recent transcriptomic analysis suggested that KRAS WT tumors may have favorable antitumor immune microenvironment characterized by increased signatures of CD8⁺ T-cell and natural killer cell infiltration (11). Preclinical research also unveiled a pivotal role for KRAS mutations in facilitating an immune suppressive environment (17, 18). Previous studies have also highlighted unique traits in KRAS WT tumors, such as high microsatellite instability and high mutational burden (11), markers of response to immunotherapy. Therefore, the next crucial step may be to gather real-world evidence to determine whether KRAS WT tumors are responsive to immunotherapy or whether specific biomarkers can predict its effectiveness in this particular group of patients. Indeed, recent clinical trials have reported efficacy in the combined inhibition of PD-1, BRAF, and MEK in patients with BRAF^V600E-mutated colorectal cancers (19). Such investigations hold great promise in advancing targeted and immunotherapy combinations for individuals with KRAS WT cancers.

Progress in targeted therapies for pancreatic cancers has lagged behind those in other major cancer types. With the emergence of KRAS inhibitors and the rise of immunotherapy, pancreatic cancer has entered the era of precision medicine. The oncogenic alterations identified in KRAS WT tumors and availability of other molecularly-targeted therapies provide a rapidly expanding treatment portfolio for pancreatic cancer. One such example is zenocutuzumab in NRG1 fusion-positive, KRAS WT pancreas cancer (20). Our next step is to efficiently deliver these biomarker-selected treatments to appropriate molecular subtypes of patients. To this end, gathering comprehensive clinical data is essential. Singh and colleagues' work sets a precedent for such future strategies to continue to improve the prognosis of pancreatic cancer. If comprehensive tumor profiling reveals WT KRAS, further investigation should be pursued to identify alternative oncogenic drivers given the potential for incorporation of targeted treatments.

H. Kato reports personal fees from Daiichi Sankyo Foundation of Life Science, The Nakatomi Foundation, and The Mochida Memorial Foundation and grants from The Andrew L. Warshaw, M.D., Institute for Pancreatic Cancer Research during the conduct of the study. No disclosures were reported by the other authors.

This work is funded by the Daiichi Sankyo Foundation of Life Science (H. Kato), The Nakatomi Foundation (H. Kato), The Mochida Memorial Foundation (H. Kato), The Andrew L. Warshaw, M.D., Institute for Pancreatic Cancer Research grant (H. Kato), and Irving W. Janock Fellowship (H. Ellis). N. Bardeesy acknowledges support from the National Institute of Health (P50CA127003 and P01CA117969) and the Linda Verville Cancer Research Foundation.