I don't think any forward player can possibly be the most efficient defensive tactic. Or at least it shouldn't be. But when you have such a top-heavy team, it's difficult not rely on the attack to do everything (including defend, ironically). I'm sympathetic to what you're saying but I see big problems with needing the heavy-hitters in attack in order to be able to defend competently.
If the team's going to rely on relieving the defence by keeping the forward pressure on, I reckon that you have to keep both Kane and Son on. The reason for Kane is his hold-up play, passing, and ridiculous ability to smartly waste time (e.g. by drawing fouls). Son stays for the rapid out-ball to get even further up the pitch (and his general ability -- maybe even add some more goals that way). That is a real mess of a situation: this squad can't afford to rely on its two best players to see out comfortable wins as well as to generate those wins.
(The way this should work was actually clearly visible in the West Ham game, but with Bale and Lucas, largely, instead of Son, neither of whom are, at this moment, as good as Son at chasing Kane's balls. It was effective, except for the part where Bale looks bereft of match fitness and Lucas just isn't anywhere near as good, so they kept giving the ball away.)
Nonetheless, it would be harsh to expect a manager to predict, let alone expect, the need for defensive pressure at 3-0. That team shouldn't have needed forward players to see out the game. I think, for that reason, the Ndombele substitution hit the worst. But it was the combination of both at the same time that really hurt. Kane basically became the midfield, yet still with attacking and defensive responsibilities. Either one of Son or Ndombele would've helped a lot with the overstretch.
Then again, at the end of it all, it didn't matter: there's just no accounting for horrible individual mistakes in defence, an own goal, and that Lanzini strike. If Jose had acted like he knew all of that was going to happen, he would've been called a madman.