With new drugs now hitting 'undruggable' targets like KRAS, which cancers are still the hardest to make progress on, and

While recent advancements have finally begun to break through the "undruggable" nature of KRAS—particularly in pancreatic cancer, where researchers are moving toward pan-RAS targeting [2]—the challenge of treating cancer remains significant.

According to current research, progress remains difficult in several areas due to biological complexity and adaptation:

• Resistance Mechanisms: Even when a target is successfully inhibited, cancer cells often find ways to survive. Mechanisms such as target mutation, pathway reactivation (where the cancer reroutes its signaling), and adaptation within the tumor microenvironment continue to challenge existing therapies [3].
• Persistent "Undruggable" Targets: Beyond KRAS, proteins like MYC and TP53 remain major hurdles. These are identified as some of the most important future targets because of how common they are in various human cancers, yet they remain notoriously difficult to hit [3].
• The Complexity of Pancreatic Cancer: While new therapies are emerging for pancreatic cancer, it remains one of the hardest cancers to treat. KRAS G12D is present in 30% to 40% of these cases [1], and because first-generation drugs focused primarily on the G12C mutation (which is rare in pancreatic cancer [1]), the field is still catching up to the specific mutations that drive this disease.

Ultimately, while the field is shifting from "undruggable" to "drugged," experts emphasize that the future of cancer treatment will likely depend on rational combination therapies—using multiple drugs simultaneously to block the ways a tumor tries to adapt or resist treatment [3].